Methods of treating virally associated cancers with histone deacetylase inhibitors

ABSTRACT

Described herein are certain dosing schedules and amounts that effectively prevent and manage side effects associated with histone deacetylase inhibitor (HDACi) treatment. Optionally, these schedules and dosing regimens include treatment with an antiviral agent.

CROSS-REFERENCE

This application claims the benefit of U.S. Provisional Application Ser.No. 62/855,454 filed on May 31, 2019, which is incorporated by referenceherein in its entirety.

SUMMARY OF THE INVENTION

Described herein are certain dosing schedules and amounts thateffectively provide efficacy and prevent and manage side effectsassociated with treatment of histone deacetylase inhibitor (HDACi)treatment. Optionally, these schedules and dosing regimens includetreatment with an antiviral agent.

Described herein, in one aspect, is a method of treating a cancer in anindividual, the method comprising administering to the individual: (a)an effective amount of a histone deacetylase inhibitor (HDACi) as aviral inducing agent, wherein the HDACi is characterized by anelimination half-life of less than 30 hours; and (b) an effective amountof an antiviral drug; wherein the individual is treated according to atreatment schedule, wherein the individual is administered a lowerdosage of the HDACi for at least one dose of the treatment schedule. Incertain embodiments, the individual is not administered the HDACi for atleast one day of the treatment schedule. In certain embodiments, theHDACi is administered orally. In certain embodiments, the HDACi isselected from the list consisting of: vorinostat, romidepsin,mocetinostat, belinostat, pracinostat, givinostat, panobinostat,CUDC-101, CDX101, chidamide, domatinostat, and nanatinostat. In certainembodiments, the HDACi inhibits activity of a class I histonedeacetylase. In certain embodiments, the HDACi is characterized by anelimination half-life of less than 24 hours. In certain embodiments, theHDACi is characterized by an elimination half-life of less than 12hours. In certain embodiments, the HDACi is characterized by anelimination half-life of less than 4 hours. In certain embodiments, theHDACi is nanatinostat. In certain embodiments, the HDACi is administeredat a total daily dose from about 10 milligrams to about 40 milligrams.In certain embodiments, the HDACi is administered at a total daily doseof about 10 milligrams. In certain embodiments, the HDACi isadministered at a total daily dose of about 15 milligrams. In certainembodiments, the HDACi is administered at a total daily dose of about 20milligrams. In certain embodiments, the HDACi is administered at a totaldaily dose of about 25 milligrams. In certain embodiments, the HDACi isadministered at a total daily dose of about 30 milligrams. In certainembodiments, the HDACi is administered once per day. In certainembodiments, the HDACi is administered twice per day. In certainembodiments, the cytotoxic activity of the antiviral agent is activatedby a viral kinase. In certain embodiments, the viral kinase comprises,an Epstein-Barr virus protein kinase, an Epstein-Barr virus thymidinekinase, a human herpes virus thymidine kinase, or a humancytomegalovirus protein. In certain embodiments, the antiviral agent isselected from the list consisting of aciclovir, ganciclovir,valaciclovir, valganciclovir, and famciclovir. In certain embodiments,the antiviral agent is valganciclovir. In certain embodiments, theantiviral agent is administered at a total daily dose of 1800milligrams. In certain embodiments, the antiviral agent is administeredat a total daily dose of 900 milligrams. In certain embodiments, theantiviral agent is administered at a total daily dose of 450 milligrams.In certain embodiments, the antiviral agent is administered every day ofthe treatment schedule. In certain embodiments, the antiviral agent isadministered orally. In certain embodiments, the individual is notadministered the HDACi for at least two days of the treatment schedule.In certain embodiments, the individual is not administered the HDACi forat least three days of the treatment schedule. In certain embodiments,the individual is not administered the HDACi for at least four days ofthe treatment schedule. In certain embodiments, the individual is notadministered the HDACi for at least five days of the treatment schedule.In certain embodiments, the treatment schedule has a duration of oneweek. In certain embodiments, the treatment schedule is repeated. Incertain embodiments, the HDACi is administered with food or a caloricsubstance. In certain embodiments, the cancer is a solid tissue cancer.In certain embodiments, the solid tissue cancer is salivary glandcancer, nasopharyngeal carcinoma, head and neck cancer, gastric cancer,a colorectal cancer, breast cancer, glioblastoma, prostate cancer, renalcancer, leiomyosarcoma, pancreatic cancer, or lung cancer. In certainembodiments, the solid tissue cancer is salivary gland cancer,nasopharyngeal carcinoma, head and neck cancer, gastric cancer, acolorectal cancer, or leiomyosarcoma. In certain embodiments, the canceris a leukemia or a lymphoma. In certain embodiments, the leukemia orlymphoma is a B cell leukemia or lymphoma. In certain embodiments, theleukemia or lymphoma is a T cell leukemia or lymphoma. In certainembodiments, the leukemia or lymphoma is non-Hodgkin's lymphoma. Incertain embodiments, the leukemia or lymphoma is Hodgkin's lymphoma. Incertain embodiments, the leukemia or lymphoma is a cytomegalovirus viruspositive leukemia or lymphoma. In certain embodiments, the leukemia orlymphoma is an Epstein-Barr virus positive leukemia or lymphoma. Incertain embodiments, the individual is afflicted with thrombocytopenia.In certain embodiments, the individual has a platelet count of less than50,000 platelets per microliter. In certain embodiments, the individualhas an elevated creatinine level. In certain embodiments, the elevatedcreatinine level exceeds 1.1 mg/dL for a woman or 1.3 mg/dL for a man.In certain embodiments, the individual is selected for treatmentaccording to the treatment schedule based on the presence ofthrombocytopenia. In certain embodiments, the individual is selectedbased on a platelet count of less than 50,000 per microliter. In certainembodiments, the individual is selected for treatment according to thetreatment schedule based on the presence of an elevated creatininelevel. In certain embodiments, the elevated creatinine level exceeds 1.1mg/dL for a woman and 1.3 mg/dL for a man.

In another aspect, described herein, is a method of treating anEpstein-Barr associated lymphoma in an individual, the method comprisingadministering to the individual: (a) an effective amount ofnanatinostat; and (b) an effective amount of valganciclovir; wherein theindividual is treated according to a treatment schedule, wherein theindividual is not administered the nanatinostat for at least three daysof the treatment schedule.

In another aspect, described herein, is a kit comprising: (a) an HDACias a viral inducing agent; and (b) an antiviral agent as a cytotoxicanti-cancer agent; wherein the kit comprises a plurality of oral dosageforms, the oral dosage forms comprising the HDACi and the antiviralagent co-packaged into separate oral dosage forms. In another aspect,described herein, is a kit comprising: (a) an HDACi; and (b) anantiviral agent; wherein the kit comprises a plurality of oral dosageforms, the oral dosage forms comprising the HDACi and the antiviralagent co-formulated into a single oral dosage form, wherein at least oneof the plurality of oral dosage forms comprises the antiviral agent anddoes not comprise the HDACi. In certain embodiments, the plurality oforal dosage forms are a pill, capsule, tablet, or gel cap. In certainembodiments, the HDACi is selected from the list consisting of:vorinostat, romidepsin, mocetinostat, belinostat, pracinostat,givinostat, panobinostat, CUDC-101, CDX101, chidamide, and nanatinostat.In certain embodiments, the HDACi inhibits activity of a class I histonedeacetylase. In certain embodiments, the HDACi is characterized by anelimination half-life of less than 24 hours. In certain embodiments, theHDACi is characterized by an elimination half-life of less than 12hours. In certain embodiments, the HDACi is characterized by anelimination half-life of less than 4 hours. In certain embodiments, theHDACi is nanatinostat. In certain embodiments, the cytotoxic activity ofthe antiviral agent is activated by a viral kinase. In certainembodiments, the viral kinase comprises, an Epstein-Barr virus proteinkinase, an Epstein-Barr virus thymidine kinase, a human herpes virusthymidine kinase, or a human cytomegalovirus protein. In certainembodiments, the antiviral agent is selected from the list consisting ofaciclovir, ganciclovir, valaciclovir, valganciclovir, and famciclovir.In certain embodiments, the antiviral agent is valganciclovir. Incertain embodiments, the plurality of oral dosage forms comprise about900 mg of valganciclovir. In certain embodiments, the plurality of oraldosage forms comprise about 450 mg of valganciclovir. In certainembodiments, the plurality of oral dosage forms comprise about 20 mg ofnanatinostat. In certain embodiments, the plurality of oral dosage formscomprise about 15 mg of nanatinostat. In certain embodiments, theplurality of oral dosage forms comprise about 10 mg of nanatinostat. Incertain embodiments, the plurality of oral dosage forms comprise sevenor a multiple thereof. In certain embodiments, one of the plurality oforal dosage forms comprises the antiviral agent and does not comprisethe HDACi. In certain embodiments, two of the plurality of oral dosageforms comprises the antiviral agent and a lower dosage amount of theHDACi. In certain embodiments, two of the plurality of oral dosage formscomprises the antiviral agent and does not comprise the HDACi. Incertain embodiments, three of the plurality of oral dosage formscomprises the antiviral agent and does not comprise the HDACi. Incertain embodiments, four of the plurality of oral dosage formscomprises the antiviral agent and does not comprise the HDACi. Incertain embodiments, five of the plurality of oral dosage formscomprises the antiviral agent and does not comprise the HDACi. Incertain embodiments, the HDACi comprises nanatinostat and the antiviralagent comprise valganciclovir.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 illustrates rapid recovery of platelet counts in patients onnanatinostat dose hold.

FIG. 2 shows comparison of the potency of nanatinostat and entinostat inperipheral blood mononuclear cells of healthy donors. Percentage ofcells with H3 acetylation, as determined by flow cytometry, is shown.

FIG. 3 shows time-course of H3 acetylation as a result of nanatinostattreatment in PBMC from healthy donors.

FIG. 4 shows the cytotoxic activity of nanatinostat was increased by˜40% when Nstat was combined with Ganciclovir. Additionally, this figureillustrates the duration of Nstat activity after 3 days of washout.

FIG. 5 illustrates non-limiting embodiments of the co-packaging andco-formulation of an HDACi and antiviral agent.

DETAILED DESCRIPTION OF THE INVENTION

There is a need for methods of treating and/or preventing viral cancersand tumors. Many patients have latent infections in which a virus ispresent, but is not expressing viral proteins such as viral thymidinekinase, viral protein kinase or viral polymerase, the target for commonanti-viral drugs such as acyclovir, ganciclovir, and valganciclovir. Avirus-inducing drug such as a histone deacetylase inhibitor (HDACinhibitor—HDACi) can be used to induce or re-induce the expression ofviral thymidine kinase, viral protein kinase, or viral polymerase invirus infected cells in the subject; the subject can then be treatedwith antiviral agents as cytotoxic cancer killing agents. As herpesvirusand/or other latent viral infections can be associated with a variety ofcancers and or tumors, activating the latent virus with HDACi incombination with antiviral agents as a cytotoxic agent is a usefultherapy in preventing or treating such conditions.

While HDACi treatment holds promise for the treatment of cancers/tumors,HDACi treatment can be associated with dose limiting toxicities thatnegatively influence treatment decisions, patient compliance, andpatient quality of life while being treated with HDACi. Some adverseeffects associated with HDACi may even limit treatment with effectivetherapies that employ HDACi. Disclosed herein are methods of treatingpatients with an HDACi that reduces side-effects associated with HDACitreatment. These methods are particularly useful for treating patientswith, or avoiding hematological side effects such as thrombocytopenia,neutropenia, Leukopenia, Anemia, or Lymphopenia. These methods are alsouseful for treating patients with, or avoiding side effects thatindicate kidney toxicity, such as elevated creatinine.

Provided herein are methods and compositions for treating viral diseasesand cancers and effectively reducing side-effects, thus improvingquality of life and expanding treatment options. The cancer or tumor canbe associated with latent viral infections. The methods can comprise thesteps of administering an HDACi to the subject. The methods can comprisethe steps of administering an HDACi and an antiviral agent to thesubject. The method can comprise steps of administering a viral geneinducing agent, an antiviral agent, and one or more additional agents toa subject. The methods may include the co-administration of an oral HDACinhibitor and an antiviral agent, either in the same or separateformulations.

The methods and compositions can be used to treat and/or prevent any ofthe cancers described herein. Any of the HDACi and/or antiviral agentsdescribed herein can be used in the methods and compositions of theprovided invention. The HDAC inhibited can be any of a class I HDAC, forinstance, HDAC1, HDAC2, and HDAC3. The HDAC inhibited can be a class IIbHDAC, for instance, HDAC10. The HDAC inhibitor can be a benzamide. Thebenzamide can be 4SC-202. The benzamide can be chidamide (also known asCS055 or HBI-8000). The HDAC inhibitor can be selected from the listconsisting of: vorinostat, romidepsin, mocetinostat, belinostat,pracinostat, givinostat, panobinostat, CUDC-101, CDX101, chidamide,domatinostat, and nanatinostat. The HDAC inhibitor can be nanatinostat.

One or more additional agents described herein can be administered to asubject. An additional agent can be selected for administration based onthe type of condition the subject has or is suspected of having.

Another aspect of the present invention relates to formulations, routesof administration and effective doses for pharmaceutical compositionscomprising an agent or combination of agents, e.g., HDACi, antiviralagents, or, optionally, one or more additional agents. An HDACi,antiviral agent or, optionally, one or more additional agents can beadministered to a subject in separate pharmaceutical compositions or canbe co-formulated in a single pharmaceutical composition. Thepharmaceutical combinations can be an oral formulation. The oralformulation can be a pill, capsule, or tablet. In certain embodiments,the pill, capsule or tablet can comprise a co-formulated dose of HDACiand antiviral agent. The anti-viral agent can be a herpes, Epstein-Barrvirus, or cytomegalovirus antiviral agent. In certain embodiments, theantiviral agent is selected from the list consisting of aciclovir,ganciclovir, valaciclovir, valganciclovir, and famciclovir. In certainembodiments, the antiviral agent is valganciclovir.

Described herein, in one aspect, is a method of treating a cancer in anindividual, the method comprising administering to the individual: (a)an effective amount of a histone deacetylase inhibitor (HDACi), whereinthe HDACi is characterized by an elimination half-life of less than 30hours; and (b) an effective amount of an antiviral drug; wherein theindividual is treated according to a treatment schedule, wherein theindividual is not administered the HDACi for at least one day of thetreatment schedule.

In another aspect, described herein, is a method of treating anEpstein-Barr associated lymphoma in an individual, the method comprisingadministering to the individual: (a) an effective amount ofnanatinostat; and (b) an effective amount of valganciclovir; wherein theindividual is treated according to a treatment schedule, wherein theindividual is not administered the nanatinostat for at least three daysof the treatment schedule.

Also provided are methods relating to dosing schedules for administeringan HDACi, an antiviral agent, or, optionally, one or more additionalagents. One or more pharmaceutical compositions can be administeredintermittently over a period of time. The schedule can encompassintermittent administration of an HDACi, and continuous administrationof an antiviral agent. The intermittent administration of the HDACi cancomprise an on and an off period, for example treating with the HDACifor 1, 2, 3, 4, or 5 days in a one-week period followed by not treatingwith the HDACi for 6, 5, 4, 3, or 2 days. Dosage for the on period canbe dose orally once a day or twice a day. Dosages applied in this typeof scheme can comprise 30, mg QD, 25 mg QD, 20 mg QD, 15 m QD, 10 mg QD,5 mg BID, 10 mg BID, or 15 mg BID.

Also described herein are kits comprising oral dosage forms formulatedto reflect the on and off period, with continuous administration of theantiviral. For example, packaging with a weeks-worth or more oftreatment, wherein the “on days” are oral dosage forms combining anHDACi and an antiviral, and the “off” days are oral dosage forms thatcomprise only the antiviral. These types of kits and packaging canincrease convenience and thus compliance for patients.

In another aspect, described herein, is a kit comprising: (a) an HDACi;and (b) an antiviral agent; wherein the kit comprises a plurality oforal dosage forms, the oral dosage forms comprising the HDACi and theantiviral agent co-formulated into a single oral dosage form, wherein atleast one of the plurality of oral dosage forms comprises the antiviralagent and does not comprise the HDACi.

Definitions

The terms “viral,” “virus-associated,” and “virally-induced” withreference to disorders are used interchangeably throughout the instantspecification.

The term “obtaining” as in “obtaining the composition” is intended toinclude purchasing, synthesizing, or otherwise acquiring the composition(or agent(s) of the composition).

The terms “comprises”, “comprising”, are intended to have the broadmeaning ascribed to them and can mean “includes”, “including” and thelike.

The term “subject”, “patient” or “individual” are used interchangeablyherein and refer to mammals and non-mammals, e.g., suffering from adisorder described herein. Examples of mammals include, but are notlimited to, any member of the Mammalian class: humans, non-humanprimates such as chimpanzees, and other apes and monkey species; farmanimals such as cattle, horses, sheep, goats, swine; domestic animalssuch as rabbits, dogs, and cats; laboratory animals including rodents,such as rats, mice and guinea pigs, and the like. Examples ofnon-mammals include, but are not limited to, birds, fish and the like.In one embodiment of the methods and compositions provided herein, themammal is a human.

The terms “treat,” “treating” or “treatment,” and other grammaticalequivalents as used herein, include alleviating, inhibiting or reducingsymptoms, reducing or inhibiting severity of, reducing incidence of,prophylactic treatment of, reducing or inhibiting recurrence of,delaying onset of, delaying recurrence of, abating or ameliorating adisease or condition symptoms, ameliorating the underlying metaboliccauses of symptoms, inhibiting the disease or condition, e.g., arrestingthe development of the disease or condition, relieving the disease orcondition, causing regression of the disease or condition, relieving acondition caused by the disease or condition, or stopping the symptomsof the disease or condition. The terms further include achieving atherapeutic benefit. By therapeutic benefit is meant eradication oramelioration of the underlying disorder being treated, and/or theeradication or amelioration of one or more of the physiological symptomsassociated with the underlying disorder such that an improvement isobserved in the patient.

Dosages are referred to herein as QD, BID or TID. QD refers to dosingonce a day. BID refers to dosing twice daily of the listed dose. TIDrefers to dosing three times a day of the listed dose. For example, 10mg BID refers to two 10 mg dosage units deliver daily. BID doses may bespaced apart such that they are at least about 16, 12, 10, or 8 hoursapart. TID doses may be spaced at about 4, 6, or 8-hour intervals.

The terms “prevent,” “preventing” or “prevention,” and other grammaticalequivalents as used herein, include preventing additional symptoms,preventing the underlying metabolic causes of symptoms, inhibiting thedisease or condition, e.g., arresting the development of the disease orcondition and are intended to include prophylaxis. The terms furtherinclude achieving a prophylactic benefit. For prophylactic benefit, thecompositions are optionally administered to a patient at risk ofdeveloping a particular disease, to a patient reporting one or more ofthe physiological symptoms of a disease, or to a patient at risk ofreoccurrence of the disease.

The terms “effective amount” or “therapeutically effective amount” asused herein, refer to a sufficient amount of at least one agent beingadministered which achieve a desired result, e.g., to relieve to someextent one or more symptoms of a disease or condition being treated. Incertain instances, the result is a reduction and/or alleviation of thesigns, symptoms, or causes of a disease, or any other desired alterationof a biological system. In certain instances, an “effective amount” fortherapeutic uses is the amount of the composition comprising an agent asset forth herein required to provide a clinically significant decreasein a disease. An appropriate “effective” amount in any individual caseis determined using any suitable technique, such as a dose escalationstudy.

The terms “administer,” “administering”, “administration,” and the like,as used herein, refer to the methods that are used to enable delivery ofagents or compositions to the desired site of biological action. Thesemethods include, but are not limited to oral routes, intraduodenalroutes, parenteral injection (including intravenous, subcutaneous,intraperitoneal, intramuscular, intravascular or infusion), topical andrectal administration. Administration techniques that in some instancesare employed with the agents and methods described herein include, e.g.,as discussed in Goodman and Gilman, The Pharmacological Basis ofTherapeutics (current edition), Pergamon; and Remington's,Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton,Pa. In certain embodiments, the agents and compositions described hereinare administered orally. In some embodiments, the compositions describedherein are administered parenterally.

The term “pharmaceutically acceptable” as used herein, refers to amaterial that does not abrogate the biological activity or properties ofthe agents described herein, and is relatively nontoxic (i.e., thetoxicity of the material significantly outweighs the benefit of thematerial). In some instances, a pharmaceutically acceptable material isadministered to an individual without causing significant undesirablebiological effects or significantly interacting in a deleterious mannerwith any of the components of the composition in which it is contained.

The term “pharmaceutically acceptable excipient,” as used herein, refersto carriers and vehicles that are compatible with the active ingredient(for example, a compound of the invention) of a pharmaceuticalcomposition of the invention (and preferably capable of stabilizing it)and not deleterious to the subject to be treated. For example,solubilizing agents that form specific, more soluble complexes with thecompounds of the invention can be utilized as pharmaceutical excipientsfor delivery of the compounds. Suitable carriers and vehicles are knownto those of extraordinary skill in the art. The term “excipient” as usedherein will encompass all such carriers, adjuvants, diluents, solvents,or other inactive additives. Suitable pharmaceutically acceptableexcipients include, but are not limited to, water, salt solutions,alcohol, vegetable oils, polyethylene glycols, gelatin, lactose,amylose, magnesium stearate, talc, silicic acid, viscous paraffin,perfume oil, fatty acid monoglycerides and diglycerides, petroethralfatty acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, etc.The pharmaceutical compositions of the invention can also be sterilizedand, if desired, mixed with auxiliary agents, e.g., lubricants,preservatives, stabilizers, wetting agents, emulsifiers, salts forinfluencing osmotic pressure, buffers, colorings, flavorings and/oraromatic substances and the like, which do not deleteriously react withthe active compounds of the invention.

The invention can be understood more fully by reference to the followingdetailed description and illustrative examples, which are intended toexemplify non-limiting embodiments of the invention.

Herpesviruses

Herpesviruses are a large family of DNA viruses that include Herpessimplex viruses (HSVs) 1 and 2, Varicella zoster virus, Epstein-Barrvirus (EBV), cytomegalovirus (CMV) and human herpesviruses (HHVs) 6A,6B, 7 and 8, which can cause various diseases in humans. Herpesviruseshave two stages of replication, the lytic and the latent. Soon afterprimary infection, immunological surveillance by the host forceherpesviruses to enter the latent state of infection, where only a fewselected genes are expressed. Conventional anti-herpesvirus drugs, suchas ganciclovir, acyclovir, etc., fail to act on these latently-infectedcells because the viral enzyme thymidine kinase (TK) or protein kinase(PK), which is necessary for the conversion of the prodrugs to theirtoxic metabolites, is not expressed in latently-infected cells. Providedherein, in some embodiments, is a combination treatment wherein lyticreplication is induced and antiviral agents are administeredconcurrently.

For example, previous studies using patient-derived cells in vitro, andalso from phase I/II clinical studies on a series of patients withEBV-associated lymphomas, have clearly shown the great promise of thiscombination therapy approach. Strong epidemiological association of EBVwith various human lymphoid malignancies and in vitro studiesdemonstrating tumorigenic activity of many EBV latent gene productssuggest a causal relationship between EBV and these diseases. However,as EBV maintains a latent state of infection in these lymphomas, typicalanti-herpesvirus drugs, such as the nucleoside analogs ganciclovir (GCV)or acyclovir, are ineffective as these pro-drugs require expression of alytic phase EBV protein, thymidine kinase (TK) or protein kinase(EBV-PK), for their activity. Therefore, selective induction of EBVlytic-phase gene expression in lymphoma cells that harbor latent EBV,coupled with simultaneous exposure to antiviral agents, has beenadvanced as promising targeted therapy, because of resulting targetingof cytotoxicity to EBV-infected tumor cells or EBV associated tumorcells.

A variety of agents including short-chain fatty acids andchemotherapeutic drugs, have been used to induce EBV lytic-phaseinfection in cultured cells, but these in vitro studies have generallynot resulted in clinical application. For instance, arginine butyrateand GCV has been used to treat EBV-positive lymphoid malignancies in arecent Phase I/II clinical trial. In this study of 15 patients withrelapsed or refractory EBV-positive lymphoid tumors, 4 patients achievedcomplete tumor remissions and 6 patients achieved partial tumorremissions. However, the rapid metabolism of butyrate requirescontinuous IV administration of high doses. Butyrate has pan-HDACinhibitory activity, and it has been established that this activity isresponsible for the induction of the EBV-TK protein. HDAC inhibitors mayinduce both EBV-TK and EBV-PK in EBV associated tumors. HDAC inhibitorsmay increase the activity of the CMV promoter in tumor cells. HDACinhibitors may increase transcription of latent Herpes simplex virusgenes in cell culture and tumors. In recent years, several potent HDACinhibitors (HDACi) have been tested in the clinic as anti-cancer agents.In some instances, HDAC inhibitors induce lytic phase gene expression inviruses and kill virus-infected cells in combination with antiviralagents. In certain instances, HDAC inhibitors, including some new,highly-potent compounds, induce EBV lytic phase gene expression and killEBV-infected cells in combination with antiviral agents. In someinstances, HDAC inhibitors induce lytic phase gene expression inherpesviruses and kill virus-infected cells in combination withantiviral agents.

Histone Deacetylase Inhibitors

The methods of the provided invention comprise use of one or morepharmaceutical compositions provided herein comprising a histonedeacetylase inhibitor (HDACi) to induce expression of a gene product ina virus-infected cell. The gene product expressed can be a viral enzymeor a cellular enzyme or activity that is largely expressed invirus-infected cells. Expression products that can be targeted includeenzymes involved with DNA replication, for example, for repair orreplication of the genome, assembly of complete virus particles,generation of viral membrane or walls, RNA transcription or proteintranslation or combinations of these activities. Interference with theseprocesses can be performed by inducing and then acting on an enzyme and,preferably, a critical enzyme in the process.

In certain embodiments, the HDACi that can be used in conjunctions withthe dosing schedules described herein is an HDACi with a shortelimination half-life. In certain embodiments, the elimination half-lifeis less than 36 hours. In certain embodiments, the elimination half-lifeis less than 30 hours. In certain embodiments, the elimination half-lifeis less than 24 hours. In certain embodiments, the elimination half-lifeis less than 16 hours. In certain embodiments, the elimination half-lifeis less than 14 hours. In certain embodiments, the elimination half-lifeis less than 12 hours. In certain embodiments, the elimination half-lifeis less than 11 hours. In certain embodiments, the elimination half-lifeis less than 10 hours. In certain embodiments, the elimination half-lifeis less than 9 hours. In certain embodiments, the elimination half-lifeis less than 8 hours. In certain embodiments, the elimination half-lifeis less than 7 hours. In certain embodiments, the elimination half-lifeis less than 6 hours. In certain embodiments, the elimination half-lifeis less than 5 hours. In certain embodiments, the elimination half-lifeis between 1 and 16 hours, 1 and 14 hours, 1 and 12 hours, 1 and 11hours, 1 and 10 hours, 1 and 9 hours, 1 and 8 hours, 1 and 7 hours, 1and 6 hours, 1 and 5 hours, or 1 and 4 hours. In certain embodiments,the elimination half-life is less than 4 hours. In certain embodiments,the elimination half-life is between 2 and 16 hours, 2 and 14 hours, 2and 12 hours, 2 and 11 hours, 2 and 10 hours, 2 and 9 hours, 2 and 8hours, 2 and 7 hours, 2 and 6 hours, 2 and 5 hours, or 2 and 4 hours. Incertain embodiments, the elimination half-life is between 3 and 16hours, 3 and 14 hours, 3 and 12 hours, 3 and 11 hours, 3 and 10 hours, 3and 9 hours, 3 and 8 hours, 3 and 7 hours, 3 and 6 hours, 3 and 5 hours,or 3 and 4 hours. In certain embodiments, the elimination half-life isbetween 4 and 16 hours, 4 and 14 hours, 4 and 12 hours, 4 and 11 hours,4 and 10 hours, 4 and 9 hours, 4 and 8 hours, 4 and 7 hours, 4 and 6hours, or 4 and 5 hours.

In some embodiments, the viral inducing agent is an HDAC inhibitor. Incertain embodiments, the HDAC inhibitor is selected from the listconsisting of: vorinostat, romidepsin, mocetinostat, belinostat,pracinostat, givinostat, panobinostat, CUDC-101, CDX101, chidamide,domatinostat, and nanatinostat. In certain embodiments, the HDACinhibitor is vorinostat. In certain embodiments, the HDAC inhibitor isromidepsin. In certain embodiments, the HDAC inhibitor is mocetinostat.In certain embodiments, the HDAC inhibitor is belinostat. In certainembodiments, the HDAC inhibitor is pracinostat. In certain embodiments,the HDAC inhibitor is givinostat. In certain embodiments, the HDACinhibitor is panobinostat. In certain embodiments, the HDAC inhibitor isCUDC-101. In certain embodiments, the HDAC inhibitor is CDX101. Incertain embodiments, the HDAC inhibitor is chidamide. In certainembodiments, the HDAC inhibitor is domatinostat. In certain embodiments,the HDAC inhibitor is nanatinostat. Nanatinostat is also referred to asCHR-3996 and VRx-3996, which is chemically identical). The chemicalformula of nanatinostat is2-((1R,5S,6s)-6-(((6-fluoroquinolin-2-yl)methyl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)-N-hydroxypyrimidine-5-carboxamide.Nanatinostat is a selective Class I HDAC inhibitor and is disclosed inU.S. Pat. No. 7,932,246, which is incorporated by reference herein inits entirety.

In some embodiments, the viral inducing agent is an HDACi. In certainembodiments, the HDACi leads to Histone 3 acetylation in the peripheralblood mononuclear cells of the individual to which it is administered.

Induced Genes Including Viral-Associated Genes

HDACi (agents that induce expression) may act directly on the viralgenome or indirectly through a cellular factor required for viralexpression. For example, viral gene expression can be regulated throughthe regulation of the expression of viral transcription factors such asZTA, RTA, tat, and tax, cellular transcription factors such as AP-1,AP-2, Sp1, NF-κB, and other transcriptional activators and/or repressors(factors), co-activators and co-repressors, histone acetylators anddeacetylators, DNA methylases and demethylases, oncogenes orproto-oncogenes, or protein kinase C. These proteins act to regulate andthereby control expression of specific viral and/or other cellulargenetic elements. According to the methods of the invention, controlover their expression can lead to control over the infection. Other geneproducts, both viral and cellular in origin, whose expression can beregulated with inducing agents include proteases, polymerases, reversetranscriptases, cell-surface receptors, major histocompatibilityantigens, growth factors, and combination of these products.

Additional genes whose expression or transcriptional regulation arealtered in the presence of butyric acid include the oncogenes myc, ras,myb, abl and src. The activities of these gene products, as well as theactivities of other oncogenes, are described in Slamon, J. D., et al.1984 Science 224:256-62. Anti-proliferative activity also includes theability to repress tumor angiogenesis through the blockade ofangiogenesis factor activity, production or release, transcriptionalregulation, or the ability to modulate transcription of genes underangiogenesis or growth factor or hormonal control. Either would be aneffective therapy, particularly against both prostatic neoplasia andbreast carcinomas. Further activities that effect transcription and/orcellular differentiation include increased intracellular cAMP levels,inhibition of histone acetylation, and inhibition of genomicmethylation. Each of these activities is directly related to geneexpression, and increased expression can sensitize infected cells to aspecific anti-viral agent.

In other embodiments, inducing agents include HDAC inhibitors thatinduce EBV-PK activity (also known BGLF4) in EBV associated tumors.Expression of EBV-PK/BGLF4 sensitizes a cell to an antiviral agent. Incertain instances, HDAC inhibitors induce EBV-PK. In some instances,HDAC inhibitors induce EBV-TK and/or EBV-PK. In some instances, HDACinhibitors induce HSV-TK and/or HSV-PK. In some instances, HDACinhibitors induce CMV-PK.

Preliminary in vitro studies according to the invention demonstrate thatinduction of EBV-TK activity in EBV-immortalized B-cells andpatient-derived tumor cells using these drugs is possible, and thatthese previously resistant cells are rendered susceptible to ganciclovirtherapy. Treatment of patients with viral-associated tumors such as EBVwith inducing agents to induce the expression of EBV-TK/EBV-PK, and GCV,to eliminate EBV-TK/EBV-PK expressing tumor cells, is an effective,non-toxic therapy. This therapeutic regimen does not depend on theassociated viral genome being the cause of the tumor. Without wishing tobe bound by theory, it is believed that just the presence of the EBVgenome in latent form would make the tumor susceptible to thiscombination protocol.

In some embodiments, an inducing agent induces viral gene expression bymore than 4fold after 24 hours of treatment. In certain embodiments, anHDAC inhibitor induces TK or EBV-PK expression by more than 4-fold after24 hours of treatment. In some embodiments, an HDAC inhibitor inducesviral gene expression after about 48 hours, about 36 hours, about 24hours, about 18 hours, about 12 hours, about 8 hours, about 6 hours,about 4 hours, about 3 hours, about 2 hours, about 1 hour, or about 30minutes. In certain embodiments, an HDAC inhibitor induces viral geneexpression in less than 48 hours, less than 36 hours, less than 24hours, less than 18 hours, less than 12 hours, less than 8 hours, lessthan 6 hours, less than 4 hours, less than 3 hours, less than 2 hours,less than 1 hours, or less than 30 minutes. In some embodiments, an HDACinhibitor induces viral gene expression in more than 48 hours, more than36 hours, more than 24 hours, more than 18 hours, more than 12 hours,more than 8 hours, more than 6 hours, more than 4 hours, more than 3hours, more than 2 hours, more than 1 hour, or more than 30 minutes. Incertain embodiments, an HDAC inhibitor induces viral gene expressionafter more than 30 minutes and less than 24 hours.

Antiviral Agents

Anti-viral agents that can be used in the compositions and methods ofthe provided invention can include, for example, substrates andsubstrate analogs, inhibitors and other agents that severely impair,debilitate or otherwise destroy virus-infected cells. Substrate analogsinclude amino acid and nucleoside analogs. Substrates can be conjugatedwith toxins or other viricidal substances. Inhibitors include integraseinhibitors, protease inhibitors, polymerase inhibitors and transcriptaseinhibitors such as reverse transcriptase inhibitors.

Antiviral agents that can be used in the compositions and methods of theprovided invention can include, for example, ganciclovir,valganciclovir, oseltamivir (Tamiflu™), zanamivir (Relenza™), abacavir,aciclovir, acyclovir, adefovir, amantadine, amprenavir, ampligen,arbidol, atazanavir, atripla, boceprevir, cidofovir, combivir,darunavir, delavirdine, didanosine, docosanol, edoxudine, efavirenz,emtricitabine, enfuvirtide, entecavir, famciclovir, fomivirsen,fosamprenavir, foscarnet, fosfonet, fusion inhibitors (e.g.,enfuvirtide), ibacitabine, imunovir, idoxuridine, imiquimod, indinavir,inosine, integrase inhibitor, interferon type III, interferon type II,interferon type I, interferon, lamivudine, lopinavir, loviride,maraviroc, moroxydine, nelfinavir, nevirapine, nexavir, nucleosideanalogues, peginterferon alfa-2a, penciclovir, peramivir, pleconaril,podophyllotoxin, protease inhibitor, raltegravir, reverse transcriptaseinhibitor, ribavirin, rimantadine, ritonavir, pyrimidine antiviral,saquinavir, stavudine, synergistic enhancer (antiretroviral), tenofovir,tenofovir disoproxil, tipranavir, trifluridine, trizivir, tromantadine,truvada, valaciclovir (Valtrex™), vicriviroc, vidarabine, viramidine,zalcitabine, and zidovudine.

In a specific embodiment, the antiviral agent is acyclovir, ganciclovir,or valganciclovir.

In some embodiments, the antiviral agent is a nucleoside analog.Examples of nucleoside analogs include acyclovir (ACV), ganciclovir(GCV), valganciclovir, famciclovir, foscarnet, ribavirin, zalcitabine(ddC), zidovudine (AZT), stavudine (D4T), lamivudine (3TC), didanosine(ddI), cytarabine, dideoxyadenosine, edoxudine, floxuridine,idozuridine, inosine pranobex, 2′-deoxy-5-(methylamino)uridine,trifluridine and vidarabine. Examples of a few protease inhibitors thatshow particular promise in human therapy include saquinivir, ritonavirand indinavir. Other anti-viral agents include interferons (e.g. α-, β-,γ-interferon), cytokines such as tumor necrosis factor (TNF) orinterleukins, cell receptors and growth factor antagonists, which can bepurified or recombinantly produced.

In some embodiments, the antiviral agent is administered at a dose ofless than 3000 mg/day. In some embodiments, the antiviral agent isadministered at a dose of about 10 mg/day, about 20 mg/day, about 50mg/day, about 100 mg/day, about 150 mg/day, about 200 mg/day, about 250mg/day, about 300 mg/day, about 350 mg/day, about 400 mg/day, about 450mg/day, about 500 mg/day, about 600 mg/day, about 700 mg/day, about 800mg/day, about 900 mg/day, about 1000 mg/day, about 1200 mg/day, about1250 mg/day, about 1400 mg/day, about 1500 mg/day, about 1600 mg/day,about 1750 mg/day, about 1800 mg/day, about 1900 mg/day, about 2000mg/day, about 2250 mg/day, about 2500 mg/day, about 2750 mg/day, about3000 mg/day, about 3250 mg/day, about 350 0 mg/day, about 3750 mg/day,about 4000 mg/day, about 4250 mg/day, about 4500 mg/day, about 4750mg/day, or about 5000 mg/day. In certain embodiments, the antiviralagent is administered at a dose of less than 10 mg/day, less than 20mg/day, less than 50 mg/day, less than 100 mg/day, less than 150 mg/day,less than 200 mg/day, less than 250 mg/day, less than 300 mg/day, lessthan 350 mg/day, less than 400 mg/day, less than 450 mg/day, less than500 mg/day, less than 600 mg/day, less than 700 mg/day, less than 800mg/day, less than 900 mg/day, less than 1000 mg/day, less than 1200mg/day, less than 1250 mg/day, less than 1400 mg/day, less than 1500mg/day, less than 1600 mg/day, less than 1750 mg/day, less than 1800mg/day, less than 1900 mg/day, less than 2000 mg/day, less than 2250mg/day, less than 2500 mg/day, less than 2750 mg/day, less than 3000mg/day, less than 3250 mg/day, less than 3500 mg/day, less than 3750mg/day, less than 4000 mg/day, less than 4250 mg/day, less than 4500mg/day, less than 4750 mg/day, or less than 5000 mg/day. In someembodiments, the antiviral agent is administered at a dose of more than10 mg/day, more than 20 mg/day, more than 50 mg/day, more than 100mg/day, more than 150 mg/day, more than 200 mg/day, more than 250mg/day, more than 300 mg/day, more than 350 mg/day, more than 400mg/day, more than 450 mg/day, more than 500 mg/day, more than 600mg/day, more than 700 mg/day, more than 800 mg/day, more than 900mg/day, more than 1000 mg/day, more than 1200 mg/day, more than 1250mg/day, more than 1400 mg/day, more than 1500 mg/day, more than 1600mg/day, more than 1750 mg/day, more than 1800 mg/day, more than 1900mg/day, more than 2000 mg/day, more than 2250 mg/day, more than 2500mg/day, more than 2750 mg/day, more than 3000 mg/day, more than 3250mg/day, more than 3500 mg/day, more than 3750 mg/day, more than 4000mg/day, more than 4250 mg/day, more than 4500 mg/day, more than 4750mg/day, or more than 5000 mg/day. In certain embodiments, the antiviralagent is administered at a dose of more than 10 mg/day and less than5000 mg/day. In some embodiments, the antiviral agent is administered ata dose of more than 200 mg/day and less than 1000 mg/day. In certainembodiments, the antiviral agent is administered once a day (q.d, QD.),twice a day (b.i.d., BID), or thrice a day (t.i.d., TID). In someembodiments, the antiviral agent is administered daily, once a week,twice a week, three times a week, four times a week, or five times aweek.

In certain embodiments, the antiviral agent is ganciclovir. In someembodiments, ganciclovir is administered at a total daily dose of 3000mg/day. In certain embodiments, ganciclovir is administered at a dose of1000 mg three times a day. In some embodiments, ganciclovir isadministered at a dose of about 100 mg/day, about 250 mg/day, about 500mg/day, about 750 mg/day, about 1000 mg/day, about 1500 mg/day, about2000 mg/day, about 2500 mg/day, about 3000 mg/day, about 3500 mg/day, orabout 4000 mg/day. In certain embodiments, ganciclovir is administeredat a dose of less than 100 mg/day, less than 250 mg/day, less than 500mg/day, less than 750 mg/day, less than 1000 mg/day, less than 1500mg/day, less than 2000 mg/day, less than 2500 mg/day, less than 3000mg/day, less than 3500 mg/day, or less than 4000 mg/day. In someembodiments, ganciclovir is administered at a dose of more than 100mg/day, more than 250 mg/day, more than 500 mg/day, more than 750mg/day, more than 1000 mg/day, more than 1500 mg/day, more than 2000mg/day, more than 2500 mg/day, more than 3000 mg/day, more than 3500mg/day, or more than 4000 mg/day. In certain embodiments, ganciclovir isadministered at a dose of more than 500 mg/day and less 4000 mg/day. Insome embodiments, ganciclovir is administered at a dose of more than1000 mg/day and less than 3000 mg/day. In some embodiments, gancicloviris administered once a day, twice a day, or three times a day. Incertain embodiments, ganciclovir is administered once a week, twice aweek, three times a week, four times a week, five times a week, ordaily.

In some embodiments, the antiviral agent is valganciclovir. In certainembodiments, valganciclovir is administered at a total daily dose of 900mg/day. In some embodiments, valganciclovir is administered at a dose of900 mg once a day. In certain embodiments, valganciclovir isadministered at a total daily dose of 1800 mg/day. In some embodiments,valganciclovir is administered at a dose of 900 mg twice a day.

Valganciclovir and other antivirals may be dosed at a lower level inresponse to certain known toxicities, such as renal or liver toxicity.Such reductions can be in accordance with label instructions Any of thedoses described herein can be reduced by 25% or 50% in response to suchtoxicities. In some embodiments, valganciclovir is administered at adose of 450 mg twice a day. In some embodiments, valganciclovir isadministered at a dose of 450 mg twice a day. In certain embodiments,antiviral treatment may be halted or one or more doses of a schedule maybe skipped in response to renal or liver toxicity. In certainembodiments, an antiviral may not be administered for one, two, three,four, five, or six days of schedule. In certain embodiments,valganciclovir may not be administered for one, two, three, four, five,or six days of schedule. In certain embodiments the schedule is sevendays.

In some embodiments, valganciclovir is administered at a dose of about100 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day, about500 mg/day, about 600 mg/day, about 700 mg/day, about 800 mg/day, about900 mg/day, about 1000 mg/day, about 1100 mg/day, about 1200 mg/day,about 1300 mg/day, about 1400 mg/day, about 1500 mg/day, about 1600mg/day, about 1700 mg/day, about 1800 mg/day, about 1900 mg/day, orabout 2000 mg/day. In certain embodiments, valganciclovir isadministered at a dose of less than 100 mg/day, less than 200 mg/day,less than 300 mg/day, less than 400 mg/day, less than 500 mg/day, lessthan 600 mg/day, less than 700 mg/day, less than 800 mg/day, less than900 mg/day, less than 1000 mg/day, less than 1100 mg/day, less than 1200mg/day, less than 1300 mg/day, less than 1400 mg/day, less than 1500mg/day, less than 1600 mg/day, less than 1700 mg/day, less than 1800mg/day, less than 1900 mg/day, or less than 2000 mg/day. In someembodiments, valganciclovir is administered at a dose of more than 100mg/day, more than 200 mg/day, more than 300 mg/day, more than 400mg/day, more than 500 mg/day, more than 600 mg/day, more than 700mg/day, more than 800 mg/day, more than 900 mg/day, more than 1000mg/day, more than 1100 mg/day, more than 1200 mg/day, more than 1300mg/day, more than 1400 mg/day, more than 1500 mg/day, more than 1600mg/day, more than 1700 mg/day, more than 1800 mg/day, more than 1900mg/day, or more than 2000 mg/day. In certain embodiments, valgancicloviris administered at a dose of more than 100 mg/day and less 2000 mg/day.In some embodiments, valganciclovir is administered at a dose of morethan 500 mg/day and less than 1500 mg/day. In some embodiments,valganciclovir is administered once a day, twice a day, or three times aday. In certain embodiments, valganciclovir is administered once a week,twice a week, three times a week, four times a week, five times a week,or daily. In certain embodiments, valganciclovir is administered dailyat a dose of about 900 milligrams. In certain embodiments,valganciclovir is administered daily at a dose of about 800 milligrams.In certain embodiments, valganciclovir is administered daily at a doseof about 700 milligrams. In certain embodiments, valganciclovir isadministered daily at a dose of about 600 milligrams. In certainembodiments, valganciclovir is administered daily at a dose of about 500milligrams. In certain embodiments, valganciclovir is administered dailyat a dose of about 450 milligrams. In certain embodiments,valganciclovir is administered daily at a dose of about 400 milligrams.In certain embodiments, the valganciclovir is administered daily even ondays when no HDACi is administered.

In certain embodiments a dosing holiday can be applied to treatment withvalganciclovir. In certain embodiments, the schedule is 7 days andvalganciclovir is not dosed for 1, 2, 3, 4, 5, or 6 days of theschedule. In certain embodiments, the schedule is 7 days andvalganciclovir is dosed at 450 mg total daily dose on 1, 2, 3, 4, 5, or6 days of the schedule. In certain embodiments, the schedule is 7 daysand valganciclovir is dosed at 900 mg total daily dose on 1, 2, 3, 4, 5,or 6 days of the schedule.

Methods and Compositions

In one aspect, provided herein are methods for treating and/orpreventing a herpesvirus associated condition. In some embodiments, thecondition is associated with a latent viral infection. In certainembodiments, the herpesvirus associated condition is a cancer. Incertain embodiments, the cancer is associated with infection by theEpstein-Barr virus. In certain embodiments, the cancer is associatedwith infection by a Herpes simplex virus. In certain embodiments, thecancer is associated with infection by a cytomegalovirus. In certainembodiments, the methods comprise administering a viral inducing agent(e.g., an HDAC inhibitor) and an antiviral agent. In some embodiments,the methods comprise administering an HDAC inhibitor and an antiviralagent. In certain embodiments, the HDAC inhibitor and the antiviralagent are co-formulated. In some embodiments, the methods compriseadministering an HDAC inhibitor and an antiviral agent. In certainembodiments, the HDAC inhibitor and the antiviral agent are formulatedseparately. In certain embodiments, the antiviral agent is administereddaily while the HDACi is administered on only certain days. In certainembodiments, the HDACi is nanatinostat. In certain embodiments, theHDACi is administered with food or another nutritional supplement. Incertain embodiments, the nanatinostat is administered with food oranother nutritional supplement. In certain embodiments, the antiviralagent is not administered for 1, 2, 3, 4, 5, 6, or 7 days of the dosageschedule.

In certain embodiments, HDACi is administered at a total daily dose ofabout 5 milligrams to about 50 milligrams. In certain embodiments, HDACiis administered at a total daily dose of about 5 milligrams to about 10milligrams, about 5 milligrams to about 15 milligrams, about 5milligrams to about 20 milligrams, about 5 milligrams to about 25milligrams, about 5 milligrams to about 30 milligrams, about 5milligrams to about 35 milligrams, about 5 milligrams to about 40milligrams, about 5 milligrams to about 45 milligrams, about 5milligrams to about 50 milligrams, about 10 milligrams to about 15milligrams, about 10 milligrams to about 20 milligrams, about 10milligrams to about 25 milligrams, about 10 milligrams to about 30milligrams, about 10 milligrams to about 35 milligrams, about 10milligrams to about 40 milligrams, about 10 milligrams to about 45milligrams, about 10 milligrams to about 50 milligrams, about 15milligrams to about 20 milligrams, about 15 milligrams to about 25milligrams, about 15 milligrams to about 30 milligrams, about 15milligrams to about 35 milligrams, about 15 milligrams to about 40milligrams, about 15 milligrams to about 45 milligrams, about 15milligrams to about 50 milligrams, about 20 milligrams to about 25milligrams, about 20 milligrams to about 30 milligrams, about 20milligrams to about 35 milligrams, about 20 milligrams to about 40milligrams, about 20 milligrams to about 45 milligrams, about 20milligrams to about 50 milligrams, about 25 milligrams to about 30milligrams, about 25 milligrams to about 35 milligrams, about 25milligrams to about 40 milligrams, about 25 milligrams to about 45milligrams, about 25 milligrams to about 50 milligrams, about 30milligrams to about 35 milligrams, about 30 milligrams to about 40milligrams, about 30 milligrams to about 45 milligrams, about 30milligrams to about 50 milligrams, about 35 milligrams to about 40milligrams, about 35 milligrams to about 45 milligrams, about 35milligrams to about 50 milligrams, about 40 milligrams to about 45milligrams, about 40 milligrams to about 50 milligrams, or about 45milligrams to about 50 milligrams. In certain embodiments, HDACi isadministered at a total daily dose of about 5 milligrams, about 10milligrams, about 15 milligrams, about 20 milligrams, about 25milligrams, about 30 milligrams, about 35 milligrams, about 40milligrams, about 45 milligrams, or about 50 milligrams. In certainembodiments, HDACi is administered at a total daily dose of at leastabout 5 milligrams, about 10 milligrams, about 15 milligrams, about 20milligrams, about 25 milligrams, about 30 milligrams, about 35milligrams, about 40 milligrams, or about 45 milligrams. In certainembodiments, HDACi is administered at a total daily dose of at mostabout 10 milligrams, about 15 milligrams, about 20 milligrams, about 25milligrams, about 30 milligrams, about 35 milligrams, about 40milligrams, about 45 milligrams, or about 50 milligrams.

In certain embodiments, nanatinostat is administered at a total dailydose of about 5 milligrams to about 50 milligrams. In certainembodiments, nanatinostat is administered at a total daily dose of about5 milligrams to about 10 milligrams, about 5 milligrams to about 15milligrams, about 5 milligrams to about 20 milligrams, about 5milligrams to about 25 milligrams, about 5 milligrams to about 30milligrams, about 5 milligrams to about 35 milligrams, about 5milligrams to about 40 milligrams, about 5 milligrams to about 45milligrams, about 5 milligrams to about 50 milligrams, about 10milligrams to about 15 milligrams, about 10 milligrams to about 20milligrams, about 10 milligrams to about 25 milligrams, about 10milligrams to about 30 milligrams, about 10 milligrams to about 35milligrams, about 10 milligrams to about 40 milligrams, about 10milligrams to about 45 milligrams, about 10 milligrams to about 50milligrams, about 15 milligrams to about 20 milligrams, about 15milligrams to about 25 milligrams, about 15 milligrams to about 30milligrams, about 15 milligrams to about 35 milligrams, about 15milligrams to about 40 milligrams, about 15 milligrams to about 45milligrams, about 15 milligrams to about 50 milligrams, about 20milligrams to about 25 milligrams, about 20 milligrams to about 30milligrams, about 20 milligrams to about 35 milligrams, about 20milligrams to about 40 milligrams, about 20 milligrams to about 45milligrams, about 20 milligrams to about 50 milligrams, about 25milligrams to about 30 milligrams, about 25 milligrams to about 35milligrams, about 25 milligrams to about 40 milligrams, about 25milligrams to about 45 milligrams, about 25 milligrams to about 50milligrams, about 30 milligrams to about 35 milligrams, about 30milligrams to about 40 milligrams, about 30 milligrams to about 45milligrams, about 30 milligrams to about 50 milligrams, about 35milligrams to about 40 milligrams, about 35 milligrams to about 45milligrams, about 35 milligrams to about 50 milligrams, about 40milligrams to about 45 milligrams, about 40 milligrams to about 50milligrams, or about 45 milligrams to about 50 milligrams. In certainembodiments, nanatinostat is administered at a total daily dose of about5 milligrams, about 10 milligrams, about 15 milligrams, about 20milligrams, about 25 milligrams, about 30 milligrams, about 35milligrams, about 40 milligrams, about 45 milligrams, or about 50milligrams. In certain embodiments, nanatinostat is administered at atotal daily dose of at least about 5 milligrams, about 10 milligrams,about 15 milligrams, about 20 milligrams, about 25 milligrams, about 30milligrams, about 35 milligrams, about 40 milligrams, or about 45milligrams. In certain embodiments, nanatinostat is administered at atotal daily dose of at most about 10 milligrams, about 15 milligrams,about 20 milligrams, about 25 milligrams, about 30 milligrams, about 35milligrams, about 40 milligrams, about 45 milligrams, or about 50milligrams.

In some embodiments, the compositions, HDACi, or antivirals areadministered on schedule in an intermittent manner. In certainembodiments, this allows for a “dose holiday” a “dose-hold” or a“structured treatment interruption,” which allows for the management ofnegative side-effects. Suitable schedules may include a total durationof a calendar week (e.g., 7 days) or any multiple thereof according tothe methods described herein. In certain embodiments, the HDACi andanti-viral agent are administered for at least one, two, three, four,five, or six days, of schedule, and no dosage amount or a reduced dosageamount of HDACi is administered for one, two, three, four, five, or sixdays of the schedule. In certain embodiments, the HDACi and anti-viralagent are administered on a 7-day schedule for at least one, two, three,four, five, or six days, of schedule, and no dosage amount or a reduceddosage amount of HDACi is administered for one, two, three, four, five,or six days of the schedule. In certain embodiments, the schedule is aweek, and is repeated until a clinically suitable outcome is determinedor reached. In certain embodiments, the schedule is a week, and isrepeated for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times. In certainembodiments, the HDACi is administered for one week followed by a weekof no administration. In certain embodiments, nanatinostat isadministered for one week followed by a week of no administration. Incertain embodiments, the antiviral is administered on every day of theschedule.

In certain embodiments, the HDACi has an elimination half-life of lessthan 34 hours. In certain embodiments, the HDACi has an eliminationhalf-life of less than 20 hours. In certain embodiments, the HDACi hasan elimination half-life of less than 12 hours. In certain embodiments,the HDACi has an elimination half-life of less than 6 hours. In certainembodiments, the HDACi has an elimination half-life of less than 4hours.

In certain embodiments, the HDACi is not detectable in the blood of asubject 48 hours after a dose is administered. In certain embodiments,the HDACi is not detectable in the blood of a subject 36 hours after adose is administered. In certain embodiments, the HDACi is notdetectable in the blood of a subject 24 hours after a dose isadministered. In certain embodiments, the HDACi is not detectable in theblood of a subject 12 hours after a dose is administered. In certainembodiments, the dose is about 50, 40, 30, 20, 15, 10, or 5 milligrams.

In certain embodiments, the dose schedule is a week, and an HDACi isadministered for 1 day of the dose schedule. In certain embodiments, thedose schedule is a week, and an HDACi is administered for 2 days of thedose schedule. In certain embodiments, the dose schedule is a week, andan HDACi is administered for 3 days of the dose schedule. In certainembodiments, the dose schedule is a week, and an HDACi is administeredfor 4 days of the dose schedule. In certain embodiments, the doseschedule is a week, and an HDACi is administered for 5 days of the doseschedule. In certain embodiments, the dose schedule is a week, and anHDACi is administered for 6 days of the dose schedule. In certainembodiments, the dose schedule is a week, and an HDACi is administeredfrom between 1 and 6 days of the dose schedule. In certain embodiments,the dose schedule is a week, and an HDACi is administered from between 2and 6 days of the dose schedule. In certain embodiments, the doseschedule is a week, and an HDACi is administered from between 3 and 6days of the dose schedule. In certain embodiments, the dose schedule isa week, and an HDACi is administered from between 4 and 6 days of thedose schedule. In certain embodiments, the dose schedule is a week, andan HDACi is administered for 5 or 6 days of the dose schedule.

In certain embodiments the dose schedule is 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28, 29, or 30 days and an HDACi is not administered for 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28, 29 days of the schedule. In certain embodiments theHDACi is nanatinostat. In certain embodiments, the antiviral isadministered on every day of the schedule, or may be reduced based onliver or kidney toxicity. In certain embodiments the antiviral isganciclovir or valganciclovir.

In certain embodiments, the dose schedule is a week, and an HDACi isadministered from between 1 and 5 days of the dose schedule. In certainembodiments, the dose schedule is a week, and an HDACi is administeredfrom between 2 and 5 days of the dose schedule. In certain embodiments,the dose schedule is a week, and an HDACi is administered from between 3and 5 days of the dose schedule. In certain embodiments, the doseschedule is a week, and an HDACi is administered for 4 or 5 days of thedose schedule.

In certain embodiments, the dose schedule is a week, and an HDACi isadministered from between 1 and 4 days of the dose schedule. In certainembodiments, the dose schedule is a week, and an HDACi is administeredfrom between 2 and 4 days of the dose schedule. In certain embodiments,the dose schedule is a week, and an HDACi is administered for 3 or 4days of the dose schedule.

In certain embodiments, the HDACi is administered QD at 30 milligrams.In certain embodiments, the HDACi is administered QD at 25 milligrams.In certain embodiments, the HDACi is administered QD at 20 milligrams.In certain embodiments, the HDACi is administered QD at 15 milligrams.In certain embodiments, the HDACi is administered QD at 10 milligrams.In certain embodiments, the HDACi is administered BID at 20 milligrams.In certain embodiments, the HDACi is administered BID at 15 milligrams.In certain embodiments, the HDACi is administered BID at 10 milligrams.In certain embodiments, the HDACi is administered BID at 5 milligrams.In certain embodiments, the HDACi is administered TID at 15 milligrams.In certain embodiments, the HDACi is administered TID at 10 milligrams.In certain embodiments, the HDACi is administered TID at 5 milligrams.In certain embodiments, the HDACi is administered TID between about 5milligrams and about 15 milligrams. In certain embodiments, an antiviralis administered daily during the schedule. In certain embodiments, theantiviral is valganciclovir, and the valganciclovir is administered at adose of 900 milligrams or 450 milligrams.

In certain embodiments, the dose schedule is a week, and an HDACi isadministered for 1 day followed by 6 days of no HDACi treatment. Incertain embodiments, the dose schedule is a week, and an HDACi isadministered for 2 days followed by 5 days of no HDACi treatment. Incertain embodiments, the dose schedule is a week, and an HDACi isadministered for 3 days followed by 4 days of no HDACi treatment. Incertain embodiments, the dose schedule is a week, and an HDACi isadministered for 4 days followed by 3 days of no HDACi treatment. Incertain embodiments, the dose schedule is a week, and an HDACi isadministered for 5 days followed by 2 days of no HDACi treatment. Incertain embodiments, the dose schedule is a week, and an HDACi isadministered for 6 days followed by 1 day of no HDACi treatment. Incertain embodiments, the dose schedule is a week, and an HDACi isadministered every other day on days 1, 2, 5, and 7. In certainembodiments, the dose schedule is a week, and an HDACi is administeredevery other day on days 2, 4, and 6. In certain embodiments, the HDACihas an elimination half-life of less than 34 hours. In certainembodiments, the HDACi has an elimination half-life of less than 20hours. In certain embodiments, the HDACi has an elimination half-life ofless than 12 hours. In certain embodiments, the HDACi has an eliminationhalf-life of less than 6 hours. In certain embodiments, an antiviral isadministered daily during the schedule. In certain embodiments, theantiviral is valganciclovir, and the valganciclovir is administered at adose of 900 milligrams or 450 milligrams.

In certain embodiments, the dose schedule is a week, and nanatinostat isadministered for 1 day of the dose schedule. In certain embodiments, thedose schedule is a week, and nanatinostat is administered for 2 days ofthe dose schedule. In certain embodiments, the dose schedule is a week,and nanatinostat is administered for 3 days of the dose schedule. Incertain embodiments, the dose schedule is a week, and nanatinostat isadministered for 4 days of the dose schedule. In certain embodiments,the dose schedule is a week, and nanatinostat is administered for 5 daysof the dose schedule. In certain embodiments, the dose schedule is aweek, and nanatinostat is administered for 6 days of the dose schedule.In certain embodiments, an antiviral is administered daily during theschedule. In certain embodiments, the antiviral is valganciclovir, andthe valganciclovir is administered at a dose of 900 milligrams or 450milligrams. In certain embodiments, the valganciclovir is notadministered for 1, 2, 3, 4, 5, 6, or 7 days of a week-long schedule.

In certain embodiments, the dose schedule is a week, and nanatinostat isadministered for 1 day followed by 6 days of no nanatinostat treatment.In certain embodiments, the dose schedule is a week, and nanatinostat isadministered for 2 days followed by 5 days of no nanatinostat treatment.In certain embodiments, the dose schedule is a week, and nanatinostat isadministered for 3 days followed by 4 days of no nanatinostat treatment.In certain embodiments, the dose schedule is a week, and nanatinostat isadministered for 4 days followed by 3 days of no HDACi treatment. Incertain embodiments, the dose schedule is a week, and nanatinostat isadministered for 5 days followed by 2 days of no nanatinostat treatment.In certain embodiments, the dose schedule is a week, and nanatinostat isadministered for 6 days followed by 1 day of no nanatinostat treatment.In certain embodiments, the dose schedule is a week, and nanatinostat isadministered every other day on days 1, 2, 5, and 7. In certainembodiments, the dose schedule is a week, and nanatinostat isadministered every other day on days 2, 4, and 6. In certainembodiments, the nanatinostat is administered QD and 30 milligrams. Incertain embodiments, the nanatinostat is administered QD at 20milligrams. In certain embodiments, the nanatinostat is administered QDat 15 milligrams. In certain embodiments, the nanatinostat isadministered QD at 10 milligrams. In certain embodiments, thenanatinostat is administered BID at 15 milligrams. In certainembodiments, the nanatinostat is administered BID at 10 milligrams. Incertain embodiments, the nanatinostat is administered BID at 5milligrams. In certain embodiments, the nanatinostat is administered TIDat 15 milligrams. In certain embodiments, the nanatinostat isadministered TID at 10 milligrams. In certain embodiments, thenanatinostat is administered TID at 5 milligrams. In certainembodiments, an antiviral is administered daily during the schedule. Incertain embodiments, an antiviral is not administered for one day of thetreatment schedule. In certain embodiments, the antiviral isvalganciclovir, and the valganciclovir is administered at a dose of 900milligrams or 450 milligrams.

In certain embodiments, the dose schedule is a week, and nanatinostat isadministered 20 mg QD for 1 day followed by 6 days of no nanatinostattreatment. In certain embodiments, the dose schedule is a week, andnanatinostat is administered 20 mg QD for 2 days followed by 5 days ofno nanatinostat treatment. In certain embodiments, the dose schedule isa week, and nanatinostat is administered 20 mg QD for 3 days followed by4 days of no nanatinostat treatment. In certain embodiments, the doseschedule is a week, and nanatinostat is administered 20 mg QD for 4 daysfollowed by 3 days of no HDACi treatment. In certain embodiments, thedose schedule is a week, and nanatinostat is administered 20 mg QD for 5days followed by 2 days of no nanatinostat treatment. In certainembodiments, the dose schedule is a week, and nanatinostat isadministered 20 mg QD for 6 days followed by 1 day of no nanatinostattreatment. In certain embodiments, the dose schedule is a week, andnanatinostat is administered every other day on days 1, 2, 5, and 7. Incertain embodiments, the dose schedule is a week, and nanatinostat isadministered every other day on days 2, 4, and 6. In certainembodiments, an antiviral is administered daily during the schedule. Incertain embodiments, the antiviral is valganciclovir, and thevalganciclovir is administered at a dose of 900 milligrams or 450milligrams.

In certain embodiments, the dose schedule is a week, and nanatinostat isadministered 10 mg QD for 1 day followed by 6 days of no nanatinostattreatment. In certain embodiments, the dose schedule is a week, andnanatinostat is administered 10 mg QD for 2 days followed by 5 days ofno nanatinostat treatment. In certain embodiments, the dose schedule isa week, and nanatinostat is administered 10 mg QD for 3 days followed by4 days of no nanatinostat treatment. In certain embodiments, the doseschedule is a week, and nanatinostat is administered 10 mg QD for 4 daysfollowed by 3 days of no HDACi treatment. In certain embodiments, thedose schedule is a week, and nanatinostat is administered 10 mg QD for 5days followed by 2 days of no nanatinostat treatment. In certainembodiments, the dose schedule is a week, and nanatinostat isadministered 10 mg QD for 6 days followed by 1 day of no nanatinostattreatment. In certain embodiments, the dose schedule is a week, andnanatinostat is administered every other day on days 1, 2, 5, and 7. Incertain embodiments, the dose schedule is a week, and nanatinostat isadministered every other day on days 2, 4, and 6. In certainembodiments, an antiviral is administered daily during the schedule. Incertain embodiments, the antiviral is valganciclovir, and thevalganciclovir is administered at a dose of 900 milligrams or 450milligrams.

In certain embodiments, the dose schedule is a week, and nanatinostat isadministered 10 mg BID for 1 day followed by 6 days of no nanatinostattreatment. In certain embodiments, the dose schedule is a week, andnanatinostat is administered 10 mg BID for 2 days followed by 5 days ofno nanatinostat treatment. In certain embodiments, the dose schedule isa week, and nanatinostat is administered 10 mg BID for 3 days followedby 4 days of no nanatinostat treatment. In certain embodiments, the doseschedule is a week, and nanatinostat is administered 10 mg BID for 4days followed by 3 days of no HDACi treatment. In certain embodiments,the dose schedule is a week, and nanatinostat is administered 10 mg BIDfor 5 days followed by 2 days of no nanatinostat treatment. In certainembodiments, the dose schedule is a week, and nanatinostat isadministered 10 mg BID for 6 days followed by 1 day of no nanatinostattreatment. In certain embodiments, the dose schedule is a week, andnanatinostat is administered every other day on days 1, 2, 5, and 7. Incertain embodiments, the dose schedule is a week, and nanatinostat isadministered every other day on days 2, 4, and 6. In certainembodiments, an antiviral is administered daily during the schedule. Incertain embodiments, an antiviral is administered at a lower dosage oncertain days of the treatment schedule. In certain embodiments, theantiviral is valganciclovir, and the valganciclovir is administered at adose of 900 milligrams or 450 milligrams.

In certain embodiments, the dose schedule is a week, and nanatinostat isadministered 5 mg BID for 1 day followed by 6 days of no nanatinostattreatment. In certain embodiments, the dose schedule is a week, andnanatinostat is administered 5 mg BID for 2 days followed by 5 days ofno nanatinostat treatment. In certain embodiments, the dose schedule isa week, and nanatinostat is administered 5 mg BID for 3 days followed by4 days of no nanatinostat treatment. In certain embodiments, the doseschedule is a week, and nanatinostat is administered 5 mg BID for 4 daysfollowed by 3 days of no HDACi treatment. In certain embodiments, thedose schedule is a week, and nanatinostat is administered 5 mg BID for 5days followed by 2 days of no nanatinostat treatment. In certainembodiments, the dose schedule is a week, and nanatinostat isadministered 5 mg BID for 6 days followed by 1 day of no nanatinostattreatment. In certain embodiments, the dose schedule is a week, andnanatinostat is administered every other day on days 1, 2, 5, and 7. Incertain embodiments, the dose schedule is a week, and nanatinostat isadministered every other day on days 2, 4, and 6. In certainembodiments, an antiviral is administered daily during the schedule. Incertain embodiments, the antiviral is valganciclovir, and thevalganciclovir is administered at a dose of 900 milligrams or 450milligrams.

The HDACi can be given with food or a meal, or a type of nutritionalsupplement. In certain embodiments, nanatinostat is given with food or ameal or a type of nutritional supplement. Dosing the HDACi with food canbe combined with the above-mentioned schedules to further increase theCmax and bioavailability of the HDACi or nanatinostat.

Also envisioned herein is dose packaging to efficiently and easilyimplement the dose schedule mentioned above. Such packaging is shown forexample in FIG. 5. The packaging can be, for example, a blister pack orother sealable packing that allows the HDACi and antiviral doses for anygiven day to be accessed. In certain embodiments, the HDACi andantiviral agent can be packaged so that the formulations of each areseparate (e.g., one day's dose comprises HDACi and antiviral agentseparated. In certain embodiments, the packing can compriseco-formulated HDACi and antiviral agent. In certain embodiments, thepacking can comprise co-formulated nanatinostat and valganciclovir. Whensuch packaging is utilized with the schedules disclosed herein, a daywhen both HDACi and antiviral agent are to be administered the packingcomprise a single oral dosage form that comprises both HDACi andantiviral agent; and a day when only an antiviral agent is to beadministered the packing can comprise antiviral agent without HDACi.When such packaging is utilized with the schedules disclosed herein, aday when both nanatinostat and valganciclovir are to be administered thepacking comprise a single oral dosage form that comprises bothnanatinostat and valganciclovir; and a day when only valganciclovir isto be administered the packing can comprise valganciclovir withoutnanatinostat.

The schedules described herein can also be administered to certainpatients with HDACi or antiviral side effects. In certain embodiments,the methods described herein encompass selecting a patent withthrombocytopenia. In certain embodiments, the methods and HDACicompositions described herein are for use in a patent withthrombocytopenia. Thrombocytopenia is generally defined as a plateletcount below 150,000 platelets per microliter. In certain embodiments,the patient can be selected for treatment by the methods herein with aplatelet count of below about 50,000; 75,000; 100,000, or 125,000platelets per microliter. In certain embodiments, the methods do notencompass a set schedule of HDACi administration, but further monitoringfor resolution of thrombocytopenia before retreatment with HDACi. Incertain embodiments, if a patient has one or more dose interruptions forHDACi toxicity or has had to interrupt for more than 14 days, themethods described herein include a dose reduction for the HDACiinhibitor. In certain embodiments with a dose reduction, the HDACi willcomprise nanatinostat and the dose reduction will be in 5 mg increments.In certain embodiments, the HDACi dose is re-escalated.

The schedules described herein can also be administered to certainpatients with HDACi or antiviral side effects. In certain embodiments,the methods described herein encompass selecting a patent with highcreatinine levels or another marker of impaired kidney function. Incertain embodiments, the methods and HDACi compositions described hereinare for use in a patent with high creatinine levels or another marker ofimpaired kidney function. A serum creatinine level that exceeds 1.1mg/dL for a woman or 1.3 mg/dL for a man is generally consideredelevated. In certain embodiments, an individual is selected to receiveHDACi and antiviral according to the schedule described herein if theypossess a serum creatinine level that exceeds 1.1 mg/dL for a woman or1.3 mg/dL for a man. In certain embodiments, a patient can be selectedto receive HDACi and antiviral according to the schedule describedherein if they possess a blood urea nitrogen level in excess of thenormal range. In certain embodiments, 20 milligrams per deciliter BUNexceeds the normal range.

The dosing schedules of HDACi and antivirals described herein can alsobe deployed prospectively to prevent certain side-effects in at riskindividuals. In certain embodiments, a patient can be selected toreceive HDACi and antiviral according to a schedule described herein ifthey possess a risk factor for compromised kidney function orthrombocytopenia. Risk factors for compromised kidney function comprisepreexisting kidney disease, receipt of a kidney transplant, diabetes,high blood pressure, family history of kidney disease, advanced age, orAfrican-American, Asian, Native American, or Hispanic ethnicity. Riskfactors for thrombocytopenia comprise previous treatment withchemotherapy or radiation therapy, a history of anemia orthrombocytopenia.

In certain embodiments, the individual selected to be treated by themethods and schedules described herein is positive for the humanimmunodeficiency virus (HIV).

Types of Viruses and Virally-Induced Cancers

The methods and compositions provided herein can be used to treat and/orprevent viral associated cancers. The virus causing the infection can bea member of the herpesvirus family, a human immunodeficiency virus,parvovirus, or coxsackie virus. A member of the herpesvirus family canbe herpes simplex virus, herpes genitalis virus, varicella zoster virus,Epstein-Barr virus, human herpesvirus 6, human herpesvirus 8, orcytomegalovirus. The subject can have coronary artery conditionassociated with a cytomegalovirus or herpes simplex virus infection. Thesubject can have an autoimmune condition associated with Epstein-Barrvirus infection. The subject can have a lymphoma or other cancerassociated with Epstein-Barr virus infection. The subject can have alymphoma or other cancer associated with human herpesvirus 8 infection.The subject can have an autoimmune condition associated with Herpessimplex virus infection. The subject can have a cancer associate withherpes simplex virus. The subject can have an autoimmune conditionassociated with cytomegalovirus infection. The subject can have alymphoma or other cancer associated with cytomegalovirus infection.

The method described herein can be used to treat a solid tumor orcancer. In certain embodiments, the solid cancer or tumor is associatedwith Epstein-Barr virus or cytomegalovirus. In certain embodiments, thesolid cancer is salivary gland cancer, nasopharyngeal carcinoma, headand neck cancer, gastric cancer, a colorectal cancer, breast cancer,glioblastoma, prostate cancer, renal cancer, pancreatic cancer, or lungcancer. In certain embodiments, the solid tumor or cancer is herein thesolid tissue cancer is salivary gland cancer, nasopharyngeal carcinoma,head and neck cancer, gastric cancer, a colorectal cancer, orleiomyosarcoma. In certain embodiments, the solid tumor or cancer issalivary gland cancer. In certain embodiments, the solid tumor or canceris nasopharyngeal carcinoma. In certain embodiments, the solid tumor orcancer is head and neck cancer. In certain embodiments, the solid tumoror cancer is Kaposi's sarcoma. In certain embodiments, the solid tumoror cancer is gastric cancer. In certain embodiments, the solid tumor orcancer is colorectal cancer. In certain embodiments, the solid tumor orcaner is positive for Epstein-Barr virus. In certain embodiments, thesolid tumor or caner is positive for cytomegalovirus.

The method described herein can be used to treat a hematologic tumor orcancer. In certain embodiments, the hematologic tumor or cancercomprises leukemia or a lymphoma. In certain embodiments, the leukemiaor lymphoma is associated with Epstein-Barr virus or cytomegalovirus. Incertain embodiments, the hematologic cancer is leukemia or a lymphoma.In certain embodiments, the leukemia or lymphoma is a B cell leukemia orlymphoma. In certain embodiments, the leukemia or lymphoma is a T cellleukemia or lymphoma. In certain embodiments, the leukemia or lymphomais non-Hodgkin's lymphoma. In certain embodiments, the leukemia orlymphoma is Hodgkin's lymphoma. In certain embodiments, the leukemia orlymphoma is a cytomegalovirus virus positive leukemia or lymphoma. Incertain embodiments, the leukemia or lymphoma is an Epstein-Barr viruspositive leukemia or lymphoma.

Formulations, Routes of Administration, and Effective Doses

Another aspect of the present invention relates to formulations, routesof administration and effective doses for pharmaceutical compositionscomprising an agent or combination of agents. Such pharmaceuticalcompositions can be used to treat a virus-induced cancer or tumor asdescribed above. A pharmaceutical composition can comprise a viralinducing agent. A pharmaceutical composition can comprise a viralinducing agent and one or more additional agents. A pharmaceuticalcomposition can comprise an antiviral agent. A pharmaceuticalcomposition can comprise an antiviral agent and one or more additionalagents. A pharmaceutical composition can comprise a viral inducing agentand an antiviral agent. A pharmaceutical composition can comprise aviral inducing agent, an antiviral agent, and one or more additionalagents.

The agents or their pharmaceutically acceptable salts can be providedalone or in combination with one or more other agents or with one ormore other forms. For example, a formulation can comprise one or moreagents in particular proportions, depending on the relative potencies ofeach agent and the intended indication. For example, in compositions fortargeting two different targets and where potencies are similar, about a1:1 ratio of agents can be used. The two forms can be formulatedtogether, in the same dosage unit, e.g., in one cream, suppository,tablet, capsule, enteric coated tablet or capsule, aerosol spray, orpacket of powder to be dissolved in a beverage; or each form may beformulated in a separate unit, e.g., two creams, two suppositories, twotablets, two capsules, a tablet and a liquid for dissolving the tablet,two aerosol sprays, or a packet of powder and a liquid for dissolvingthe powder, etc.

A “pharmaceutically acceptable salt” can be a salt that retains thebiological effectiveness and properties of one or more agents, and whichare not biologically or otherwise undesirable. For example, apharmaceutically acceptable salt does not interfere with the beneficialeffect of a viral inducing agent or an antiviral agent.

Salts can include those of the inorganic ions, for example, sodium,potassium, calcium, magnesium ions, and the like. Salts can includesalts with inorganic or organic acids, for example, hydrochloric acid,hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid,methanesulfonic acid, p-toluenesulfonic acid, acetic acid, fumaric acid,succinic acid, lactic acid, mandelic acid, malic acid, citric acid,tartaric acid or maleic acid. If one or more agents contain a carboxygroup or other acidic group, it can be converted into a pharmaceuticallyacceptable addition salt with inorganic or organic bases. Examples ofsuitable bases include sodium hydroxide, potassium hydroxide, ammonia,cyclohexylamine, dicyclohexyl-amine, ethanolamine, diethanolamine,triethanolamine, and the like.

A pharmaceutically acceptable ester or amide can be an ester or amidethat retains biological effectiveness and properties of one or moreagents, and which are not biologically or otherwise undesirable. Forexample, the ester or amide does not interfere with the beneficialeffect of a viral inducing agent, an antiviral agent, or an additionalagent. Esters can include, for example, ethyl, methyl, isobutyl,ethylene glycol, and the like. Amides include can include, for example,unsubstituted amides, alkyl amides, dialkyl amides, and the like.

One or more agents and/or combinations of agents can be administeredwith still other agents. The choice of agents that can beco-administered with the agents and/or combinations of agents candepend, at least in part, on the condition being treated. Agents ofparticular use in the formulations of the present invention include, forexample, any agent having a therapeutic effect for a virus-inducedcancer or tumor, including, e.g., drugs used to treat inflammatoryconditions. For example, formulations of the instant invention canadditionally contain one or more conventional anti-inflammatory drugs,such as an NSAID, e.g., ibuprofen, naproxen, acetominophen, ketoprofen,or aspirin. In some alternative embodiments, for the treatment of avirus-induced inflammatory condition can additionally contain one ormore conventional influenza antiviral agents, such as amantadine,rimantadine, zanamivir, and oseltamivir. In treatments for retroviralinfections, such as HIV, formulations of the instant invention mayadditionally contain one or more conventional antiviral drug, such asprotease inhibitors (lopinavir/ritonavir {Kaletra™}, indinavir{Crixivan™}, ritonavir {Norvir™}, nelfinavir {Viracept™}, saquinavirhard gel capsules {Invirase™}, atazanavir {Reyataz™}, amprenavir{Agenerase™}, fosamprenavir {Telzir™}, tipranavir{Aptivus™}), reversetranscriptase inhibitors, includingnon-Nucleoside andNucleoside/nucleotide inhibitors (AZT {zidovudine, Retrovir™}, ddI{didanosine, Videx™}, 3TC {lamivudine, Epivir™}, d4T {stavudine,Zerit™}, abacavir {Ziagen™}, FTC {emtricitabine, Emtriva™}, tenofovir{Viread™}, efavirenz {Sustiva™} and nevirapine {Viramune™}), fusioninhibitors T20 {enfuvirtide, Fuzeon™}, integrase inhibitors (MK-0518 andGS-9137), and maturation inhibitors (PA-457 {Bevirimat™}). As anotherexample, formulations can additionally contain one or more supplements,such as vitamin C, E or other anti-oxidants.

One or more agents (or pharmaceutically acceptable salts, esters oramides thereof) can be administered per se or in the form of apharmaceutical composition wherein the one or more active agent(s) is inan admixture or mixture with one or more pharmaceutically acceptablecarriers. A pharmaceutical composition, as used herein, can be anycomposition prepared for administration to a subject. Pharmaceuticalcompositions can be formulated in conventional manner using one or morephysiologically acceptable carriers, comprising excipients, diluents,and/or auxiliaries, e.g., that facilitate processing of the activeagents into preparations that can be administered. Proper formulationcan depend at least in part upon the route of administration chosen. Oneor more agents, or pharmaceutically acceptable salts, esters, or amidesthereof, can be delivered to a patient using a number of routes or modesof administration, including oral, buccal, topical, rectal, transdermal,transmucosal, subcutaneous, intravenous, and intramuscular applications,as well as by inhalation.

For oral administration, one or more agents can be formulated readily bycombining the one or more active agents with pharmaceutically acceptablecarriers well known in the art. Such carriers can enable the one or moreagents to be formulated as tablets, including chewable tablets, pills,dragees, capsules, lozenges, hard candy, liquids, gels, syrups,slurries, powders, suspensions, elixirs, wafers, and the like, for oralingestion by a patient to be treated. Such formulations can comprisepharmaceutically acceptable carriers including solid diluents orfillers, sterile aqueous media and various non-toxic organic solvents.Generally, the agents of the invention can be included at concentrationlevels ranging from about 0.5%, about 5%, about 10%, about 20%, or about30% to about 50%, about 60%, about 70%, about 80% or about 90% by weightof the total composition of oral dosage forms, in an amount sufficientto provide a desired unit of dosage.

Aqueous suspensions for oral use can contain one or more agents withpharmaceutically acceptable excipients, such as a suspending agent(e.g., methyl cellulose), a wetting agent (e.g., lecithin, lysolecithinand/or a long-chain fatty alcohol), as well as coloring agents,preservatives, flavoring agents, and the like.

Oils or non-aqueous solvents can be required to bring one or more agentsinto solution, due to, for example, the presence of large lipophilicmoieties. Alternatively, emulsions, suspensions, or other preparations,for example, liposomal preparations, can be used. With respect toliposomal preparations, any known methods for preparing liposomes fortreatment of a condition can be used. See, for example, Bangham et al.,J. Mol. Biol. 23: 238-252 (1965) and Szoka et al., Proc. Natl Acad. Sci.USA 75: 4194-4198 (1978), incorporated herein by reference. Ligands canalso be attached to the liposomes to direct these compositions toparticular sites of action. One or more agents can also be integratedinto foodstuffs, e.g, cream cheese, butter, salad dressing, or ice creamto facilitate solubilization, administration, and/or compliance incertain patient populations.

Pharmaceutical preparations for oral use can be obtained as a solidexcipient, optionally grinding a resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients are, in particular,fillers such as sugars, including lactose, sucrose, mannitol, orsorbitol; flavoring elements, cellulose preparations such as, forexample, maize starch, wheat starch, rice starch, potato starch,gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/orpolyvinyl pyrrolidone (PVP). Disintegrating agents can be added, forexample, the cross-linked polyvinyl pyrrolidone, agar, or alginic acidor a salt thereof such as sodium alginate. One or more agents can alsobe formulated as a sustained release preparation.

Dragee cores can be provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments can be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of one or more active agents.

Pharmaceutical preparations that can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active agents can be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers can be added. All formulations fororal administration can be in dosages suitable for administration.

For injection, one or more agents can be formulated in aqueoussolutions, including but not limited to physiologically compatiblebuffers such as Hank's solution, Ringer's solution, or physiologicalsaline buffer. Such compositions can also include one or moreexcipients, for example, preservatives, solubilizers, fillers,lubricants, stabilizers, albumin, and the like. Methods of formulationare known in the art, for example, as disclosed in Remington'sPharmaceutical Sciences, latest edition, Mack Publishing Co., Easton P.

One or more agents can also be formulated as a depot preparation. Suchlong acting formulations can be administered by implantation ortranscutaneous delivery (for example subcutaneously or intramuscularly),intramuscular injection or use of a transdermal patch. Thus, forexample, one or more agents can be formulated with suitable polymeric orhydrophobic materials (for example as an emulsion in an acceptable oil)or ion exchange resins, or as sparingly soluble derivatives, forexample, as a sparingly soluble salt.

Pharmaceutical compositions comprising one or more agents can exertlocal and regional effects when administered topically or injected at ornear particular sites of infection. Direct topical application, e.g., ofa viscous liquid, gel, jelly, cream, lotion, ointment, suppository,foam, or aerosol spray, can be used for local administration, toproduce, for example local and/or regional effects. Pharmaceuticallyappropriate vehicles for such formulation include, for example, loweraliphatic alcohols, polyglycols (e.g., glycerol or polyethylene glycol),esters of fatty acids, oils, fats, silicones, and the like. Suchpreparations may also include preservatives (e.g., p-hydroxybenzoic acidesters) and/or antioxidants (e.g., ascorbic acid and tocopherol). Seealso Dermatological Formulations: Percutaneous absorption, Barry (Ed.),Marcel Dekker Incl, 1983. In some embodiments, local/topicalformulations comprising a viral inducing agent and or antiviral agentare used to treat epidermal or mucosal viral-induced inflammatorycondition.

Pharmaceutical compositions can contain a cosmetically ordermatologically acceptable carrier. Such carriers can be compatiblewith skin, nails, mucous membranes, tissues and/or hair, and can includeany conventionally used cosmetic or dermatological carrier meeting theserequirements. Such carriers can be readily selected by one of ordinaryskill in the art. In formulating skin ointments, an agent or combinationof agents can be formulated in an oleaginous hydrocarbon base, ananhydrous absorption base, a water-in-oil absorption base, anoil-in-water water-removable base and/or a water-soluble base.

The compositions according to the present invention can be in any formsuitable for topical application, including aqueous, aqueous-alcoholicor oily solutions, lotion or serum dispersions, aqueous, anhydrous oroily gels, emulsions obtained by dispersion of a fatty phase in anaqueous phase (O/W or oil in water) or, conversely, (W/O or water inoil), microemulsions or alternatively microcapsules, microparticles orlipid vesicle dispersions of ionic and/or nonionic type. Thesecompositions can be prepared according to conventional methods. Theamounts of the various constituents of the compositions according to theinvention can be those conventionally used in the art. Thesecompositions constitute protection, treatment or care creams, milks,lotions, gels or foams for the face, for the hands, for the body and/orfor the mucous membranes, or for cleansing the skin. The compositionscan also consist of solid preparations constituting soaps or cleansingbars.

A pharmaceutical composition can also contain adjuvants common to thecosmetic and dermatological fields, for example, hydrophilic orlipophilic gelling agents, hydrophilic or lipophilic active agents,preserving agents, antioxidants, solvents, fragrances, fillers,sunscreens, odor-absorbers and dyestuffs. The amounts of these variousadjuvants can be those conventionally used in the fields considered and,for example, are from about 0.01% to about 20% of the total weight ofthe composition. Depending on their nature, these adjuvants can beintroduced into the fatty phase, into the aqueous phase and/or into thelipid vesicles.

Ocular viral infections can be effectively treated with ophthalmicsolutions, suspensions, ointments or inserts comprising an agent orcombination of agents of the present invention.

In some embodiments, viral infections of the ear can be effectivelytreated with otic solutions, suspensions, ointments or insertscomprising an agent or combination of agents of the present invention.

One or more agents can be delivered in soluble rather than suspensionform, which can allow for more rapid and quantitative absorption to thesites of action. In general, formulations such as jellies, creams,lotions, suppositories and ointments can provide an area with moreextended exposure to the agents of the present invention, whileformulations in solution, e.g., sprays, provide more immediate,short-term exposure.

Relating to topical/local application, a pharmaceutical composition caninclude one or more penetration enhancers. For example, the formulationscan comprise suitable solid or gel phase carriers or excipients thatincrease penetration or help delivery of agents or combinations ofagents of the invention across a permeability barrier, e.g., the skin.Many of these penetration-enhancing compounds are known in the art oftopical formulation, and include, e.g., water, alcohols (e.g., terpeneslike methanol, ethanol, 2-propanol), sulfoxides (e.g., dimethylsulfoxide, decylmethyl sulfoxide, tetradecylmethyl sulfoxide),pyrrolidones (e.g., 2-pyrrolidone, N-methyl-2-pyrrolidone,N-(2-hydroxyethyl)pyrrolidone), laurocapram, acetone, dimethylacetamide,dimethylformamide, tetrahydrofurfuryl alcohol, L-α-amino acids, anionic,cationic, amphoteric or nonionic surfactants (e.g., isopropyl myristateand sodium lauryl sulfate), fatty acids, fatty alcohols (e.g., oleicacid), amines, amides, clofibric acid amides, hexamethylene lauramide,proteolytic enzymes, α-bisabolol, d-limonene, urea andN,N-diethyl-m-toluamide, and the like. Additional examples includehumectants (e.g., urea), glycols (e.g., propylene glycol andpolyethylene glycol), glycerol monolaurate, alkanes, alkanols, ORGELASE,calcium carbonate, calcium phosphate, various sugars, starches,cellulose derivatives, gelatin, and/or other polymers. A pharmaceuticalcomposition can include one or more such penetration enhancers.

A pharmaceutical composition for local/topical application can includeone or more antimicrobial preservatives, for example, quaternaryammonium compounds, organic mercurials, p-hydroxy benzoates, aromaticalcohols, chlorobutanol, and the like.

Gastrointestinal viral infections can be effectively treated withorally- or rectally delivered solutions, suspensions, ointments, enemasand/or suppositories comprising an agent or combination of agents of thepresent invention.

Respiratory viral infections can be effectively treated with aerosolsolutions, suspensions or dry powders comprising an agent or combinationof agents of the present invention. Administration by inhalation isparticularly useful in treating viral infections of the lung, such asinfluenza. The aerosol can be administered through the respiratorysystem or nasal passages. For example, one skilled in the art willrecognize that a composition of the present invention can be suspendedor dissolved in an appropriate carrier, e.g., a pharmaceuticallyacceptable propellant, and administered directly into the lungs using anasal spray or inhalant. For example, an aerosol formulation comprisinga viral inducing agent and/or antiviral agent can be dissolved,suspended or emulsified in a propellant or a mixture of solvent andpropellant, e.g., for administration as a nasal spray or inhalant.Aerosol formulations may contain any acceptable propellant underpressure, such as a cosmetically or dermatologically or pharmaceuticallyacceptable propellant, as conventionally used in the art.

An aerosol formulation for nasal administration is generally an aqueoussolution designed to be administered to the nasal passages in drops orsprays. Nasal solutions can be similar to nasal secretions in that theyare generally isotonic and slightly buffered to maintain a pH of about5.5 to about 6.5, although pH values outside of this range canadditionally be used. Antimicrobial agents or preservatives can also beincluded in the formulation.

An aerosol formulation for inhalations and inhalants can be designed sothat an agent or combination of agents can be carried into therespiratory tree of the subject when administered by the nasal or oralrespiratory route. Inhalation solutions can be administered, forexample, by a nebulizer. Inhalations or insufflations, comprising finelypowdered or liquid drugs, can be delivered to the respiratory system asa pharmaceutical aerosol of a solution or suspension of the agent orcombination of agents in a propellant, e.g., to aid in disbursement.Propellants can be liquefied gases, including halocarbons, for example,fluorocarbons such as fluorinated chlorinated hydrocarbons,hydrochlorofluorocarbons, and hydrochlorocarbons, as well ashydrocarbons and hydrocarbon ethers.

Halocarbon propellants can include fluorocarbon propellants in which allhydrogens are replaced with fluorine, chlorofluorocarbon propellants inwhich all hydrogens are replaced with chlorine and at least onefluorine, hydrogen-containing fluorocarbon propellants, andhydrogen-containing chlorofluorocarbon propellants. Halocarbonpropellants are described in Johnson, U.S. Pat. No. 5,376,359, issuedDec. 27, 1994; Byron et al., U.S. Pat. No. 5,190,029, issued Mar. 2,1993; and Purewal et al., U.S. Pat. No. 5,776,434, issued Jul. 7, 1998.Hydrocarbon propellants useful in the invention include, for example,propane, isobutane, n-butane, pentane, isopentane and neopentane. Ablend of hydrocarbons can also be used as a propellant. Etherpropellants include, for example, dimethyl ether as well as the ethers.An aerosol formulation of the invention can also comprise more than onepropellant. For example, an aerosol formulation can comprise more thanone propellant from the same class, such as two or more fluorocarbons;or more than one, more than two, more than three propellants fromdifferent classes, such as a fluorohydrocarbon and a hydrocarbon.Pharmaceutical compositions of the present invention can also bedispensed with a compressed gas, e.g., an inert gas such as carbondioxide, nitrous oxide or nitrogen.

Aerosol formulations can also include other components, for example,ethanol, isopropanol, propylene glycol, as well as surfactants or othercomponents such as oils and detergents. These components can serve tostabilize the formulation and/or lubricate valve components.

The aerosol formulation can be packaged under pressure and can beformulated as an aerosol using solutions, suspensions, emulsions,powders and semisolid preparations. For example, a solution aerosolformulation can comprise a solution of an agent, such as a viralinducing agent and/or antiviral agent in (substantially) pure propellantor as a mixture of propellant and solvent. The solvent can be used todissolve the agent and/or retard the evaporation of the propellant.Solvents useful in the invention include, for example, water, ethanoland glycols. Any combination of suitable solvents can be used,optionally combined with preservatives, antioxidants, and/or otheraerosol components.

An aerosol formulation can also be a dispersion or suspension. Asuspension aerosol formulation may comprise a suspension of an agent orcombination of agents of the instant invention, e.g., a viral inducingagent and/or antiviral agent, and a dispersing agent. Dispersing agentsuseful in the invention include, for example, sorbitan trioleate, oleylalcohol, oleic acid, lecithin and corn oil. A suspension aerosolformulation can also include lubricants, preservatives, antioxidant,and/or other aerosol components.

An aerosol formulation can be formulated as an emulsion. An emulsionaerosol formulation can include, for example, an alcohol such asethanol, a surfactant, water and a propellant, as well as an agent orcombination of agents, e.g., a viral inducing agent and/or an antiviralagent. The surfactant used can be nonionic, anionic or cationic. Oneexample of an emulsion aerosol formulation comprises, for example,ethanol, surfactant, water and propellant. Another example of anemulsion aerosol formulation comprises, for example, vegetable oil,glyceryl monostearate and propane.

Pharmaceutical compositions suitable for use in the present inventioncan include compositions wherein the active ingredients are present inan effective amount, i.e., in an amount effective to achieve therapeuticand/or prophylactic benefit in a host with at least one virus-inducedinflammatory condition. The actual amount effective for a particularapplication will depend on the condition or conditions being treated,the condition of the subject, the formulation, and the route ofadministration, as well as other factors known to those of skill in theart. Determination of an effective amount of a viral inducing agentand/or antiviral agent is well within the capabilities of those skilledin the art, in light of the disclosure herein, and can be determinedusing routine optimization techniques.

An effective amount for use in humans can be determined from animalmodels. For example, a dose for humans can be formulated to achievecirculating, liver, topical and/or gastrointestinal concentrations thathave been found to be effective in animals. One skilled in the art candetermine the effective amount for human use, especially in light of theanimal model experimental data described herein. Based on animal data,and other types of similar data, those skilled in the art can determinean effective amount of a composition appropriate for humans.

An effective amount when referring to an agent or combination of agentsof the invention can generally mean the dose ranges, modes ofadministration, formulations, etc., that have been recommended orapproved by any of the various regulatory or advisory organizations inthe medical or pharmaceutical arts (e.g., FDA, AMA) or by themanufacturer or supplier.

Further, appropriate doses for a viral inducing agent and/or antiviralagent can be determined based on in vitro experimental results.

A person of skill in the art would be able to monitor in a patient theeffect of administration of a particular agent. For example, HIV or EBVviral load levels can be determined by techniques standard in the art,such as measuring CD4 cell counts, and/or viral levels as detected byPCR. Other techniques would be apparent to one of skill in the art.

This disclosure provides for a kit, the kits can comprise one or morecontainers, the kit can comprise any combination of HDAC inhibitors,antivirals or additional agents mentioned in the methods of thisdisclosure in suitable packaging. The kit may contain instructions foruse. The HDAC inhibitor or antiviral can be present in any concentrationdisclosed herein, can be packaged for administration by any routedisclosed herein, or in any formulation disclosed herein. In someembodiments, the HDAC inhibitor and antiviral agent are packagedtogether, in a suitable package or container, in a kit. The kit may befor convenient administration or dosing, and management thereof. In somefurther embodiments, the HDAC inhibitor and antiviral are formulatedtogether as a pharmaceutical composition in a single dose. In somealternative embodiments, the HDAC inhibitor and antiviral are formulatedas separate pharmaceutical compositions. In some embodiments, thepharmaceutical composition of the HDAC inhibitor is packaged for once aweek, twice a week, thrice a week, four times a week or more, once amonth, twice a month, thrice a month, four times a month or more dosing;and the pharmaceutical composition of the antiviral is packaged fordaily, twice daily, thrice daily, four times a day or more dosing. Insome embodiments, the antiviral is administered or taken without theHDAC inhibitor. In some embodiments, the treatment course of the HDACinhibitor and antiviral can be as follows: the HDAC inhibitor and theantiviral are taken or administered together in the same pharmaceuticalcomposition on any of the first, second, third, fourth, fifth or moredays of treatment; and the antiviral is taken or administered by itselfon any of days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or more. In somefurther embodiments, the treatment course can be as follows: the HDACinhibitor and antiviral are taken or administered separately indifferent pharmaceutical composition on any of the first, second, third,fourth, fifth or more days of treatment, either at the same time ortemporally separated by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or morehours; and the antiviral is taken or administered by itself on any ofdays 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or more. In someembodiments, the HDAC inhibitor packaged in the kit is nanatinostat. Insome embodiments, the antiviral is ganciclovir, in other embodiments, itis valganciclovir. In some embodiments, the treatment course is repeatedfor 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or more iterations.

The kits described herein may comprise a plurality of oral dosage forms,wherein the oral dosage form comprises an HDACi and an antiviral. Incertain embodiments, the plurality comprises seven or a multiplethereof. In certain embodiments, the kit comprises one oral dosage formcomprising HDACi and antiviral co-formulated into a single form, and sixoral dosage forms comprising an antiviral and no or a reduced amount ofHDACi. In certain embodiments, the kit comprises two oral dosage formscomprising HDACi and antiviral co-formulated into a single form, andfive oral dosage forms comprising an antiviral and no or a reducedamount of HDACi. In certain embodiments, the kit comprises three oraldosage forms comprising HDACi and antiviral co-formulated into a singleform, and four oral dosage forms comprising an antiviral and no or areduced amount of HDACi. In certain embodiments, the kit comprises fouroral dosage forms comprising HDACi and antiviral co-formulated into asingle form, and three oral dosage forms comprising an antiviral and noor a reduced amount of HDACi. In certain embodiments, the kit comprisesfive oral dosage forms comprising HDACi and antiviral co-formulated intoa single form, and two oral dosage forms comprising an antiviral and noor a reduced amount of HDACi. In certain embodiments, the kit comprisessix oral dosage forms comprising HDACi and antiviral co-formulated intoa single form, and one oral dosage form comprising an antiviral and noor a reduced amount of HDACi. The package may suitably comprise amultiple of seven of any of these amounts (e.g., kits providing one,two, or three-months' worth of dosage). The oral dosage forms may becompounded for dosing once a day, twice a day, or three times daily. Incertain embodiments, the HDACi comprises nanatinostat. In certainembodiments, the amount of nanatinostat incorporated into the oraldosage form comprises 5 milligrams, 10 milligrams, 15 milligrams, 20milligrams, 25 milligrams, 30 milligrams. In certain embodiments, theantiviral comprises valganciclovir. In certain embodiments, the amountof valganciclovir incorporated into the oral dosage form comprises 450milligrams, 900 milligrams, or 1,800 milligrams.

The kits described herein may comprise a plurality of oral dosage forms,wherein the oral dosage form comprises an HDACi and an antiviralformulated separately. In certain embodiments, the kit comprises atleast two oral dosage form comprising HDACi and antiviral formulatedseparately, and six oral dosage forms comprising an antiviral and no ora reduced amount of HDACi. In certain embodiments, the kit comprisesfour oral dosage forms comprising HDACi and antiviral formulatedseparately, and five oral dosage forms comprising an antiviral and no ora reduced amount of HDACi. In certain embodiments, the kit comprises sixoral dosage forms comprising HDACi and antiviral formulated separately,and four oral dosage forms comprising an antiviral and no or a reducedamount of HDACi. In certain embodiments, the kit comprises eight oraldosage forms comprising HDACi and antiviral formulated separately, andthree oral dosage forms comprising an antiviral and no or a reducedamount of HDACi. In certain embodiments, the kit comprises ten oraldosage forms comprising HDACi and antiviral formulated separately, andtwo oral dosage forms comprising an antiviral and no or a reduced amountof HDACi. In certain embodiments, the kit comprises twelve oral dosageforms comprising HDACi and antiviral formulated separately, and one oraldosage form comprising an antiviral and no or a reduced amount of HDACi.The package may suitably comprise a multiple of seven of any of theseamounts (e.g., kits providing one, two, or three-months' worth ofdosage). The oral dosage forms may be compounded for dosing once a day,twice a day, or three times daily. In certain embodiments, the HDACicomprises nanatinostat. In certain embodiments, the amount ofnanatinostat incorporated into the oral dosage form comprises 5milligrams, 10 milligrams, 15 milligrams, 20 milligrams, 25 milligrams,30 milligrams. In certain embodiments, the antiviral comprisesvalganciclovir. In certain embodiments, the amount of valganciclovirincorporated into the oral dosage form comprises 450 milligrams, 900milligrams, or 1,800 milligrams.

The kits of this invention are in suitable packaging. Suitable packagingincludes, but is not limited to, vials, bottles, jars, flexiblepackaging (e.g., sealed Mylar, blister packs, plastic bags), and thelike. Also contemplated are packages for use in combination with aspecific device, such as an inhaler, nasal administration device (e.g.,an atomizer) or an infusion device such as a minipump. A kit may have asterile access port (for example the container may be an intravenoussolution bag or a vial having a stopper pierceable by a hypodermicinjection needle). The container may also have a sterile access port(for example the container may be an intravenous solution bag or a vialhaving a stopper pierceable by a hypodermic injection needle). At leastone active agent in the composition is an HDAC inhibitor. The HDACinhibitor can be nanatinostat. The container may further comprise asecond pharmaceutically active agent. This second pharmaceuticallyactive agent can be an antiviral. The antiviral can be ganciclovir orvalganciclovir.

Examples Example 1—Clinical Trial Combining HDACi and AntiviralTreatment

Nanatinostat (Nstat) (VRx-3996 formerly known as CHR-3996) is a Class1-selective, oral, hydroxamate histone deacetylase (HDAC) inhibitoractive against HDAC 1-3 but not HDAC 6.

Ontract (NCT03397706) is a Phase 1b/2, open-label, dose-escalation (3+3design) study followed by an expansion stage at the recommended Phase 2dose (RP2D) of p.o. N+VG in patients with EBV-associated lymphomas. Doseschedules tested are shown in Table 1 below.

TABLE 1 Dose schedules and amounts Phase 1b Escalation CohortDose/Schedule 1 N 10 mg BID, daily VG 900 mg BID 2a N 5 mg BID, daily VG450 mg BID 2b N 10 mg QD, daily VG 450 mg BID 2c N 10 mg QD, daily VG900 mg QD 3 N 20 mg QD × 4 days per week VG 900 mg QD (3 days off);weekly × 4

Primary Objectives

-   -   Phase 1b: Determine the safety, tolerability, and R2PD of N+VG    -   Phase 2: Evaluate the safety and tolerability of the R2PD and        assess the objective response rate (ORR) by Recommendations for        Initial Evaluation, Staging, and Response Assessment of Hodgkin        and Non-Hodgkin Lymphoma: The Lugano Classification⁷ (Lugano)        and RECIL 2017⁸ by central review

Secondary Objectives

-   -   Phase 1b/2: Evaluate pharmacokinetics (PK) of N and PK of        ganciclovir    -   Phase 2: Evaluate time to tumor response, duration of response,        time to tumor progression, and progression-free survival        Exploratory Outcomes    -   Phase 1b/2: Evaluate changes in viral loads (CMV, EBV, HHV-6,        HHV-8, HIV) as appropriate, EBV latency/lytic profile and genome        methylation status, changes in histone H3 acetylation (PBMCs)

Key Eligibility Criteria

-   -   Relapsed/refractory, pathologically confirmed EBV+ lymphoma        (EBER-ISH) or lymphoproliferative disease regardless of        histologic subtype, including:    -   EBV-associated post-transplant lymphoproliferative disease        (PTLD) after allogeneic hematopoietic cell transplant (alloHCT)        or solid organ transplant (SOT)    -   EBV-associated lymphoproliferative disorders (LPD) and        malignancies associated with acquired immunodeficiency,        including HIV+ infections    -   EBV-associated lymphomas and LPDs not associated with        immunodeficiency    -   Presence of measurable disease    -   Age ≥18 years; ECOG performance status of 0 to 2; adequate        hematologic, renal, and hepatic function

The demographics of individuals enrolled in the trial are shown in Table2 and the dosing by Cohort and intensity is shown in Table 3 below.

TABLE 2 Demographics and Lymphoma Characteristics Patients Enrolled (n)25 Male/Female 18/7 Median Age, (Range), yrs 58 (19-84) ECOG PS, 0, 1,or 2 8, 15, 2 Median Prior Therapies, 2 (1 -9) n (Range) Irradiation  6Transplant, n (%) 9 [7, 1, 1] [Auto, Allo, Both] HDACi 3 (2 =Romidepsin, 1 Belinosat) Median Day-1 Platelets, 174 (64-327) 10⁹/L,(Range) Lymphoma type B cell (12 total) T-cell (8 total) DLBCL (5)Extranodal NK/T Cell Lymphoma (3) Plasmablastic lymphoma (2) CutaneousT-cell lymphoma (1) Burkitt's (1) Anaplastic T cell (3)Lymphoplasmacytic LPD (1) Peripheral T-cell lymphoma Post-transplant nototherwise specified (1) lymphoproliferative disorders (1) Other (2)Hodgkin's (5) HIV+ 4 (20%)

TABLE 3 Dosing by Cohort and Intensity Cohort 1 2a 2b 2c Total Daily N20 mg N 10 mg Dose VG 1800 mg VG 900 mg Schedule 10 BID 5 BID 10 QD 10QD 900 BID 450 BID 450 BID 900 QD Patients (n) 7 5 4 4 N 28-Day MedianDaily 13.8 mg 8.8 mg 10 mg 7.8 mg Dose Intensity, (%) (69%) (88%) (100%)(78%) [range] [9.3-20] [0-10] [1-10] [0-10] *VG starting dose adjustedfor renal function per prescribing guidelines

Cohort 1 (10 mg, BID) exceeded the maximum tolerated doses based on 4different hematologic dose limiting toxicities in 2 patients. No doselimiting toxicities and fewer dose holds were observed in cohort 2 (5 mgBID or 10 mg QD). Thrombocytopenia was the most common dose limitingtoxicity as shown in Table 4. Platelet nadirs rapidly recovered after 3to 5 days of dose hold. See FIG. 1. This indicated that treatmentaccording to a schedule where patients were treated with HDACi for 1, 2,3, 4, or 5 days; and not treated for 6, 5, 4, 3, or 2 day might limithematologic side effects like thrombocytopenia.

TABLE 4 Cohort 3 (N = 5) + Phase 2 (N = 8) Cohort 1 (N = 7) Cohort 2abc(N = 13) at the RP2D [Nstat 20 mg, [Nstat 10 mg, [Nstat 20 mg (4/7 d),Adverse Event VGCV 1800 mg] VGCV 900 mg] VGCV 900 mg] N (%) HematologicThrombocytopenia 3 (43%) 2 (15%) 0 Neutropenia 2 (28%) 2 (15%) 1 (8%)Anemia 1 (14%) 1 (8%)  1 (8%) Non-Hematologic Creatinine 0 0 0 ElevationFatigue 1 (14%) 0 0 Nstat = nanatinostat; VGCV = valganciclovir; 4/7 d =4 days of treatment in 7 day schedule

Overall, Objective responses were observed in all dose cohorts andacross B- and T-cell lymphomas. See Table 5. Evidence of antitumoractivity was observed by PET in 10 of 18 patients evaluable by PET.Major responses have been observed at the first scan at week 8.Interestingly, pseudo-progression was observed in two patients atapproximately month 4 were followed by major responses (CR, PR), and mayindicate immune surveillance response. In two patients, progression inthe skin was observed while maintaining a CR or PR systemic response.One patient who had skin clearing 2 weeks after therapy discontinuedtreatment and has remained disease free. In HIV+ patients, 3 of 3evaluable have progressed

TABLE 5 Best HIV-negative Response All (n = 18) All B Cell T cell NKcell Hodgkin CR 5 5 2 1 1 1 PR 5 5 2 2 2 0 SD 4 4 1 0 0 3 PD 4 1 1 0 0 0Total 18 15 5 3 3 4 CR = complete response; PR = partial response; SD =stable disease; PD = progressive disease

Example 2-Nstat is More Potent than Other HDACi and Treatment Results inLong Term Histone Acetylation

Nanatinostat has T_(1/2) of approximately 2 hours, as shown in Table 6,in experiments conducted in humans. Patients enrolled in study wereadministered oral nanatinostat and valganciclovir at predefined doses.Blood samples for pharmacokinetic studies were drawn on cycle 1 day 1 at30 minutes, 1, 2, 4 6 and 24 hours after the first dose of nanatinostat.Serum concentration of nanatinostat were assayed at Inotiv, Inc. and PKparameters, including terminal half-life calculated using PhoenixWinNonlin v. 8.1 software.

TABLE 6 Geometric Mean (% CV) Single Dose Pharmacokinetics of VRx-3996after Different Treatments Treatment A B C Parameter N Mean % CV N Mean% CV N Mean % CV T_(max) (h)* 4 3.00 (1.00-6.00) 9 2.00 (1.00-6.00) 61.00 (0.500-6.00) C_(max) (ng/mL) 4 18.5 230 9 62.6 138 6 78.9 46.3AUC_(last) (ng-h/mL) 4 40.5 204 9 165 128 6 227 37.8 AUC (ng-h/mL) 1 117NC 1 317 NC 4 322 12.9 Half-Life (h) 1 2.18 NC 1 1.17 NC 4 1.67 21.1 A =5 mg VRx-3996 p.o. and 450 mg Valganciclovir p.o. B = 10 mg VRx-3996p.o. and 450 mg Valganciclovir p.o. C = 10 mg VRx-3996 p.o. and 900 mgValganciclovir p.o. *Median (range)

The IC₅₀ of HDAC inhibition for nanatinostat, romidepsin (FK228),entinostat (MS-275), suberanilohydroxamic acid (SAHA or vorinostat), ortrichostatin A (TSA) was determined in an in vitro histone acetylationassay. Briefly, all of the compounds are dissolved in DMSO. A series ofdilutions of the compounds were prepared with 10% DMSO in HDAC assaybuffer and 5 μl of the dilution was added to a 50 μl reaction so thatthe final concentration of DMSO is 1% in all of reactions. The compoundswere pre-incubated in duplicate at RT for 1 hour in a mixture containingHDAC assay buffer, 5 μg BSA, HDAC enzyme (see Table 7) and a theparticular HDACi. After 1 hour, the enzymatic reactions were initiatedby the addition of HDAC substrate (BPS Bioscience) to a finalconcentration of 10 μM or 2 μM. The enzymatic reaction proceeded for 30minutes at 37° C. After enzymatic reactions, 50 μl of 2×HDAC Developerwas added to each well for the HDAC enzymes and the plate was incubatedat room temperature for an additional 15 minutes. Fluorescence intensitywas measured at an excitation of 360 nm and an emission of 460 nm usinga Tecan Infinite M1000 microplate reader.

HDAC activity assays were performed in duplicates at each concentration.The fluorescent intensity data were analyzed using the computersoftware, Graphpad Prism. In the absence of the compound, thefluorescent intensity (F_(t)) in each data set was defined as 100%activity. In the absence of HDAC, the fluorescent intensity (F_(b)) ineach data set was defined as 0% activity. The percent activity in thepresence of each compound was calculated according to the followingequation: % activity=(F−F_(b))/(F_(t)−F_(b)), where F=the fluorescentintensity in the presence of the compound.

The values of % activity versus a series of compound concentrations werethen plotted using non-linear regression analysis of Sigmoidaldose-response curve generated with the equationY=B+(T−B)/1+10^(((LogEC50−X)×Hill Slope)), where Y=percent activity,B=minimum percent activity, T=maximum percent activity, X=logarithm ofcompound and Hill Slope=slope factor or Hill coefficient. The IC₅₀ valuewas determined by the concentration causing a half-maximal percentactivity.

TABLE 7 Enzyme Used Assay (ng)/Reaction Substrate HDAC1 7.2 10 μM HDACSubstrate 3 HDAC2 7.5 10 μM HDAC Substrate 3 HDAC3/NCOR2 3.4 10 μM HDACSubstrate 3 HDAC4 0.3  2 μM HDAC Substrate Class 2a HDAC5 40  2 μM HDACSubstrate Class 2a HDAC6 10 10 μM HDAC Substrate 3 HDAC7 1.6  2 μM HDACSubstrate Class 2a HDAC8 25  2 μM HDAC Substrate Class 2a HDAC9 4.3  2μM HDAC Substrate Class 2a HDAC11 60  2 μM HDAC Substrate Class 2a

Results for these experiments are shown in Table 8. Overall, incomparison to other HDACi, Nstat shows high potency inhibition of HDAC1,HDAC2, HDAC4, HDAC5, HDAC8, and HDAC9 when compared to all other HDACitested.

TABLE 8 IC₅₀ (μM) or Percentage Inhibition Enzymes Nstat FK228 MS-275SAHA TSA HDAC1 0.0036 1.2 0.19 0.087 — HDAC2 0.012 8.4 0.31 0.099 —HDAC3/NCOR2 0.012 4.3 0.28 0.078 — HDAC4 1 >100 NI* @ 100 μM >100 NI @100 μM >100 34% @ 100 μM 4.5 HDAC5 0.39 >100 17% @ 100 μM >100 NI @ 100μM ~48 3.4 HDAC6 0.45 0.74 ~66 0.011 — HDAC7 1.6 >100 NI @ 100 μM >100NI @ 100 μM >100 27% @ 100 μM 1.4 HDAC8 0.86 ~63 >100 NI @ 100 μM ~461.6 HDAC9 0.44 >100 NI @ 100 μM >100 NI @ 100 μM >100 37% @ 100 μM 4.1HDAC11 2.8 >100 NI @ 100 μM >100 NI @ 100 μM ~49 2.1

Nanatinostat has high potency as an HDAC and a short half-life comparedto many HDACi. Given these properties nanatinostat might be able to bedeployed on an intermittent schedule or a schedule with a dose hold. Todetermine if it was feasible to implement a dose hold from apharmacokinetic standpoint the peripheral blood mononuclear cells wereisolated from healthy volunteers and treated with either nanatinostat orentinostat (an HDACi with an elimination of half-life of approximately36 hours). Since H3 acetylation is a pharmacodynamic biomarker of Nstatactivity, acetylation of H3 was examined in treated cells. As shown inFIG. 2, Nstat was much more potent than entinostat in inducing elevatedlevels of Histone 3 acetylation, even at a dose of 100 nM. As shown inFIG. 3, this effect on H3 acetylation was long-lasting even at dosesdown to 10 nM.

Nanatinostat increases cell cytotoxicity in an EBV infected cell linewhen combined with ganciclovir. This effect is seen even after Nstatremoval as shown in FIG. 4. P3HR1 Burkitt's lymphoma cells wereincubated with DMSO (solvent control) or Nstat for 3 days. After thattime cell cultures were washed re-fed with ganciclovir (GCV) for anadditional 3 days. All test conditions were run in triplicate. Celldeath was measured by 7AAD staining.

Overall, these data and experiments provide rational that a dose holidayof an, HDACi like Nstat, can be implemented to adequately controladverse reactions while maintaining therapeutic efficiency.

Example 3—Clinical Trial Combining HDACi and Antiviral Treatment

The below example is a description of an open-label, dose escalation andexpansion study of orally administered nanatinostat and valganciclovirin subjects with advanced, Epstein-Barr virus-associated solidmalignancies.

Study Population

Patients with locally advanced or metastatic, EBV-associated, solidtumors including, but not limited to:

-   -   EBV-associated gastric adenocarcinoma    -   EBV-associated nasopharyngeal carcinoma

Primary Objectives

-   -   Determine the safety and tolerability of        nanatinostat/valganciclovir    -   Determine a recommended Phase 2 dose (RP2D) of        nanatinostat/valganciclovir    -   Assess activity based on objective response rate (ORR)

Secondary Objectives

-   -   Evaluate pharmacokinetic (PK) parameters for nanatinostat    -   Evaluate PK parameters for valganciclovir    -   Evaluate time to response    -   Evaluate duration of response    -   Evaluate progression-free survival (PFS)    -   Evaluate overall survival (OS)

Exploratory Objectives

-   -   Evaluate changes in viral loads by quantitative polymerase chain        reaction with treatment (cytomegalovirus, EBV) where applicable    -   Evaluate EBV latency/lytic profile

Treatment Regimen

The initial dose of nanatinostat will be 20 mg daily for 4 out of 7 dayseach week in a 4-week cycle, with dose escalation cohorts to 30 mg and40 mg daily based on tolerability and lack of DLT. Valganciclovir willbe administered continuously at 900 mg daily. The doses may be packagedin a weekly blister package. See FIG. 5.

Study Design

A 2-part, Phase 1b/2 study to define a RP2D of nanatinostat incombination with valganciclovir (Phase 1b) and then to evaluate theefficacy of this combination in advanced solid malignancies (Phase 2).Phase 1b (dose escalation) will follow a rolling six design, in which upto 6 patients will be enrolled at each dose cohort:

-   -   If 3 patients complete a 28-day cycle with no DLT, then the next        cohort can be enrolled    -   If 1 DLT is observed, the cohort will be expanded to include 6        to 8 patients.    -   If 1 DLT in 6 patients is observed, then the cohort will be        considered to have acceptable safety and the next cohort will be        opened for enrollment.    -   If 2 DLT in six patients are observed then the MTD has been        exceeded.

Patients who do not complete the first 28-day cycle for reasons otherthan study drug toxicity may be replaced. Phase 2 (expansion) up to 30additional patients will be enrolled to confirm tolerability of the RP2Dand ORR. All patients (Phase 1b and 2) will be assessed for responseusing RECIST 1.1 criteria. The clinical trial will enroll up to 50patients.

Key Inclusion Criteria

-   -   Patients with a histologically or cytologically confirmed        diagnosis of locally advanced or metastatic EBV-associated solid        tumor for whom standard therapy is not effective, available,        acceptable, or is intolerable    -   Must have evaluable disease or at least one measurable lesion on        computed tomography (CT) scan or magnetic resonance imaging (MM)        per RECIST 1.1    -   Males or females aged ≥18 years at screening    -   Screening laboratory values:        -   Hemoglobin ≥9 g/dL        -   Absolute neutrophil count ≥1500 cells/mm3        -   Platelet count ≥100,000 cells/mm3        -   Total bilirubin ≤1.5×ULN        -   Aspartate aminotransferase and alanine aminotransferase            ≤2.5×ULN. (unless liver metastases are present then up to            5×ULN allowed)        -   Serum creatinine ≤1.5 mg/dL or estimated glomerular            filtration rate (eGFR) ≥60 mL/min/1.73 m2        -   International Normalized Ratio (INR) or Prothrombin Time            (PT) ≤1.5×ULN (unless patient is receiving anticoagulant            therapy as long as PT or PTT is within therapeutic range of            intended use of anticoagulants)        -   Activated Partial Thromboplastin Time (aPTT) ≤1.5×ULN            (unless patient is receiving anticoagulant therapy as long            as PT or PTT is within therapeutic range of intended use of            anticoagulants)    -   Patients with treated, stable CNS metastases (including        leptomeningeal carcinomatosis) are allowed, if there is no        evidence of progression for at least 4 weeks after CNS-directed        treatment as ascertained by clinical examination and brain        imaging. The use of seizure prophylaxis is allowed    -   Resolution of any clinically significant toxic effects of prior        therapy to Grade 0 or 1 according to the National Cancer        Institute Common Terminology Criteria for Adverse Events (NCI        CTCAE), version 5.0 (exception of alopecia and Grade 2        peripheral neuropathy)    -   Eastern Cooperative Oncology Group (ECOG) performance status of        ≤2

Example 4-Nanatinostat Tablet Formulation

According to the methods and kits described herein, Nanatinostat can beformulated as a single agent, immediate release tablet. Non-limitingexamples of formulations of dosages in a single agent tablet are shownin Table 10 below. The manufacturing process is a typical pharmaceuticalgranulation/blend/compression/coating process.

TABLE 9 Formula % Weight per Weight per Weight per Materials Functionw/w Tablet (5 mg) Tablet (10 mg) Tablet (20 mg) Nanatinostat Active 5.00 5.00 10.00 20.0 Pharmaceutical Ingredient Mannitol Filler 25.00 25.0050.00 50.0 Microcrystalline Filler 65.50 65.50 131    262.0  CelluloseCroscarmellose Disintegrant 4.0 4.0  8.0  16.0 Sodium Sodium StearylLubricant 0.5 0.5  1  2  Fumarate Total of tablet core: 100.00 100 mg200 mg 400 mg Non-functional coating  3 mg  6 mg  12 mg Total of coatedtablet 103 mg 206 mg 412 mg

Example 5—Co-Formulations of HDACi and Antivirals

Experiments were undertaken to develop immediate release, fixed dosingtablet formulations with an anti-viral and an HDACi. These experimentsevaluated Bulk/Tap Density, Particle Size Distribution, BlendUniformity, Hardness, and Disintegration time of Tablets. Agranulation/blend/compression/coating pharmaceutical manufacturingprocess was developed to manufacture fixed dose tablets with variousratio and strength. One embodiment of fixed dose tablet of 20 mgNanatinostat/450 mg Valganciclovir is shown in Table 10.

TABLE 10 Fixed dose tablet of 20 mg Nanatinostat/450 mg ValganciclovirIngredients % w/w mg/tablet Valganciclovir 79.4%  496.30 Hydrochloride(450 free base equivalent) Nanatinostat 3.2% 20.00 Microcrystalline10.2%  63.20 Cellulose Povidone 2.2% 14.00 Crospovidone 3.4% 21.00Magnesium Stearate 1.6% 10.50 Total 100%  625.0

The dissolution profile of fixed dose tablet of 20 mg Nanatinostat/450mg Valganciclovir is shown in Table 11.

TABLE 11 Dissolution of Fixed dose tablet of 20 mg Nanatinostat/450 mgValganciclovir Nanatinstat Dissolution Valganciclovir Dissolution Timepoint Time point (min) % Release (min) % Release 10 12 10 46 20 30 20 7530 47 30 90 45 64 45 100 60 75 60 102 75 82 75 102 90 89 — —

Experiments were also conducted to manufacture the tablet with differentstrengths and ratios, evaluate any process modifications and optimizethe powder blend for flow properties, particle size and density. Theresultant tablets from the final blend were characterized physically(Compression Profile) chemically (Assay/Impurities, Water Content,Dissolution) and placed on long term stability studies. The formulationformula of two, immediate release, fixed dose tablets, i.e, 10 mgNanatinostat/450 mg Valganciclovir and 20 mg Nanatinostat/900 mgValganciclovir are shown in Table 12.

TABLE 12 Fixed dose tablets 10 mg Nanatinostat/ 20 mg Nanatinostat/ %450 mg Valganciclovir 900 mg Valganciclovir Material w/w mg/tabletmg/tablet Nanatinostat 1.6 10.0 20.0 Valganciclovir 79.4 496.3 992.6 HCL(450 free base equivalent) Microcrystalline 11.8 73.2 146.4 CellulosePovidone K30 2.2 14.0 28.0 Crospovidone 3.4 21.0 42.0 Magnesium 1.610.50 21.0 Stearate Total 100.0 625.0 1250 Coating Non-functional 3.018.8 coating Total 103.0 643.8

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention.

All publications, patent applications, issued patents, and otherdocuments referred to in this specification are herein incorporated byreference as if each individual publication, patent application, issuedpatent, or other document was specifically and individually indicated tobe incorporated by reference in its entirety. Definitions that arecontained in text incorporated by reference are excluded to the extentthat they contradict definitions in this disclosure.

What is claimed is:
 1. A method of treating a cancer in an individual,the method comprising administering to the individual: (a) an effectiveamount of a histone deacetylase inhibitor (HDACi), wherein the HDACi ischaracterized by an elimination half-life of less than 30 hours; and (b)an effective amount of an antiviral drug; wherein the individual istreated according to a treatment schedule, wherein the individual is notadministered the HDACi for at least one dose of the treatment schedule.2. The method of claim 1, wherein the individual is not administered theHDACi for at least one day of the treatment schedule
 3. The method ofclaim 1 or 2, wherein the HDACi is administered orally.
 4. The method ofany one of claims 1 to 3, wherein the HDACi is selected from the listconsisting of: vorinostat, romidepsin, mocetinostat, belinostat,pracinostat, givinostat, panobinostat, CUDC-101, CDX101, chidamide,domatinostat, and nanatinostat.
 5. The method of any one of claims 1 to4, wherein the HDACi inhibits activity of a class I histone deacetylase.6. The method of any one of claims 1 to 5, wherein the HDACi ischaracterized by an elimination half-life of less than 24 hours.
 7. Themethod of any one of claims 1 to 5, wherein the HDACi is characterizedby an elimination half-life of less than 12 hours.
 8. The method of anyone of claims 1 to 5, wherein the HDACi is characterized by anelimination half-life of less than 4 hours.
 9. The method of any one ofclaims 1 to 8, wherein the HDACi is nanatinostat.
 10. The method of anyone of claims 1 to 9, wherein the HDACi is administered at a total dailydose from about 10 milligrams to about 40 milligrams.
 11. The method ofclaim 10, wherein the HDACi is administered at a total daily dose ofabout 10 milligrams.
 12. The method of claim 10, wherein the HDACi isadministered at a total daily dose of about 15 milligrams.
 13. Themethod of claim 10, wherein the HDACi is administered at a total dailydose of about 20 milligrams.
 14. The method of claim 10, wherein theHDACi is administered at a total daily dose of about 25 milligrams. 15.The method of claim 10, wherein the HDACi is administered at a totaldaily dose of about 30 milligrams.
 16. The method of any one of claims10 to 15, wherein the HDACi is administered once per day.
 17. The methodof any one of claims 1 to 16, wherein the cytotoxic activity of theantiviral agent is activated by a viral kinase.
 18. The method of claim17, wherein the viral kinase comprises, an Epstein-Barr virus proteinkinase, an Epstein-Barr virus thymidine kinase, a human herpes virusthymidine kinase, or a human cytomegalovirus protein.
 19. The method ofany one of claims 1 to 18, wherein the antiviral agent is selected fromthe list consisting of aciclovir, ganciclovir, valaciclovir,valganciclovir, and famciclovir.
 20. The method of claim 19, wherein theantiviral agent is valganciclovir.
 21. The method of any one of claims 1to 20, wherein the antiviral agent is administered at a total daily doseof 1,800 milligrams.
 22. The method of any one of claims 1 to 20,wherein the antiviral agent is administered at a total daily dose of 900milligrams.
 23. The method of any one of claims 1 to 20, wherein theantiviral agent is administered at a total daily dose of 450 milligrams.24. The method of any one of claims 1 to 23, wherein the antiviral agentis administered every day of the treatment schedule.
 25. The method ofany one of claims 1 to 23, wherein the antiviral agent is notadministered on one or more days of the treatment schedule.
 26. Themethod of any one of claims 1 to 25, wherein the antiviral agent isadministered orally.
 27. The method of any one of claims 1 to 26,wherein the individual is not administered the HDACi for at least twodays of the treatment schedule.
 28. The method of any one of claims 1 to26, wherein the individual is not administered the HDACi for at leastthree days of the treatment schedule.
 29. The method of any one ofclaims 1 to 26, wherein the individual is not administered the HDACi forat least four days of the treatment schedule.
 30. The method of any oneof claims 1 to 26, wherein the individual is not administered the HDACifor at least five days of the treatment schedule.
 31. The method of anyone of claims 1 to 30, wherein the treatment schedule has a duration ofone week.
 32. The method of any one of claims 1 to 31, wherein thetreatment schedule is repeated.
 33. The method of any one of claims 1 to32, wherein the HDACi is administered with food or a caloric substance.34. The method of any one of claims 1 to 33, wherein the cancer is asolid tissue cancer.
 35. The method of claim 34, wherein the solidtissue cancer is salivary gland cancer, nasopharyngeal carcinoma, headand neck cancer, gastric cancer, a colorectal cancer, breast cancer,glioblastoma, prostate cancer, renal cancer, leiomyosarcoma, pancreaticcancer, or lung cancer.
 36. The method of claim 34, wherein the solidtissue cancer is salivary gland cancer, nasopharyngeal carcinoma, headand neck cancer, gastric cancer, a colorectal cancer, or leiomyosarcoma.37. The method of any one of claims 1 to 33, wherein the cancer is aleukemia or a lymphoma.
 38. The method of claim 37, wherein the leukemiaor lymphoma is a B cell leukemia or lymphoma.
 39. The method of claim37, wherein the leukemia or lymphoma is a T cell leukemia or lymphoma.40. The method of claim 37, wherein the leukemia or lymphoma isnon-Hodgkin's lymphoma.
 41. The method of claim 37, wherein the leukemiaor lymphoma is Hodgkin's lymphoma.
 42. The method of claim 37, whereinthe leukemia or lymphoma is a cytomegalovirus virus positive leukemia orlymphoma.
 43. The method of claim 37, wherein the leukemia or lymphomais an Epstein-Barr virus positive leukemia or lymphoma.
 44. The methodof any one of claims 1 to 43, wherein the individual is afflicted withthrombocytopenia.
 45. The method of claim 44, wherein the individual hasa platelet count of less than 150,000 platelets per microliter.
 46. Themethod of claim 44, wherein the individual has a platelet count of lessthan 50,000 platelets per microliter.
 47. The method of any one ofclaims 1 to 43, wherein the individual has an elevated creatinine level.48. The method of claim 47, wherein the elevated creatinine levelexceeds 1.1 mg/dL for a woman or 1.3 mg/dL for a man.
 49. The method ofany one of claims 1 to 48, wherein the individual is selected fortreatment according to the treatment schedule based on the presence ofthrombocytopenia.
 50. The method of claim 48, wherein the individual isselected based on a platelet count of less than 50,000 per microliter.51. The method of any one of claims 1 to 48, wherein the individual isselected for treatment according to the treatment schedule based on thepresence of an elevated creatinine level.
 52. The method of claim 51,wherein the elevated creatinine level exceeds 1.1 mg/dL for a woman and1.3 mg/dL for a man.
 53. A method of treating an Epstein-Barr associatedlymphoma in an individual, the method comprising administering to theindividual: (a) an effective amount of nanatinostat; and (b) aneffective amount of valganciclovir; wherein the individual is treatedaccording to a treatment schedule, wherein the individual is notadministered the nanatinostat for at least three days of the treatmentschedule.
 54. The method of claim 53, wherein the individual is notadministered the nanatinostat for at least four days of the treatmentschedule.
 55. The method of claim 53, wherein the individual is notadministered the nanatinostat for at least five days of the treatmentschedule.
 56. A kit comprising: a) an HDACi; and b) an antiviral agent;wherein the kit comprises a plurality of oral dosage forms, wherein theoral dosage forms comprising the HDACi and the antiviral agent areco-packaged or co-formulated into a single oral dosage form, wherein atleast one of the plurality of oral dosage forms comprises the antiviralagent and does not comprise the HDACi.
 57. The kit of claim 56, whereinthe kit comprises a plurality of oral dosage forms, wherein the oraldosage forms comprising the HDACi and the antiviral agent areco-packaged.
 58. The kit of claim 56, wherein the kit comprises aplurality of oral dosage forms, wherein the oral dosage forms comprisingthe HDACi and the antiviral agent are co-formulated.
 59. The kit of anyone of claims 56 to 58, wherein the plurality of oral dosage forms are apill, capsule, tablet, or gel cap.
 60. The kit of any one of claims 56to 59, wherein the HDACi is selected from the list consisting of:vorinostat, romidepsin, mocetinostat, belinostat, pracinostat,givinostat, panobinostat, CUDC-101, chidamide, domatinostat, andnanatinostat.
 61. The kit of any one of claims 56 to 60, wherein theHDACi inhibits activity of a class I hi stone deacetylase.
 62. The kitof any one of claims 56 to 61, wherein the HDACi is characterized by anelimination half-life of less than 24 hours.
 63. The kit of any one ofclaims 56 to 61, wherein the HDACi is characterized by an eliminationhalf-life of less than 12 hours.
 64. The kit of any one of claims 56 to61, wherein the HDACi is characterized by an elimination half-life ofless than 4 hours.
 65. The kit of any one of claims 56 to 64, whereinthe HDACi is nanatinostat.
 66. The kit of any one of claims 56 to 65,wherein the cytotoxic activity of the antiviral agent is activated by aviral kinase.
 67. The kit of claim 66, wherein the viral kinasecomprises, an Epstein-Barr virus protein kinase, an Epstein-Barr virusthymidine kinase, a human herpes virus thymidine kinase, or a humancytomegalovirus protein.
 68. The kit of any one of claims 56 to 67,wherein the antiviral agent is selected from the list consisting ofaciclovir, ganciclovir, valaciclovir, valganciclovir, and famciclovir.69. The kit of claim 67, wherein the antiviral agent is valganciclovir.70. The kit of any one of claims 56 to 69, wherein the plurality of oraldosage forms comprises about 1,800 mg of valganciclovir.
 71. The kit ofany one of claims 56 to 69, wherein the plurality of oral dosage formscomprises about 900 mg of valganciclovir.
 72. The kit of any one ofclaims 56 to 70, wherein the plurality of oral dosage forms comprisesabout 450 mg of valganciclovir.
 73. The kit of any one of claims 56 to71, wherein the plurality of oral dosage forms comprises about 20 mg ofnanatinostat.
 74. The kit of any one of claims 56 to 71, wherein theplurality of oral dosage forms comprises about 15 mg of nanatinostat.75. The kit of any one of claims 56 to 71, wherein the plurality of oraldosage forms comprises about 10 mg of nanatinostat.
 76. The kit of anyone of claims 56 to 75, wherein the plurality comprises seven or amultiple thereof.
 77. The kit of claim 76, wherein at least one of theplurality of oral dosage forms comprises the antiviral agent and doesnot comprise the HDACi.
 78. The kit of claim 76, wherein at least one ofthe plurality of oral dosage forms comprises the HDACi and does notcomprise the antiviral agent.
 79. The kit of claim 76, wherein two ofthe plurality of oral dosage forms comprises the antiviral agent anddoes not comprise the HDACi.
 80. The kit of claim 76, wherein three ofthe plurality of oral dosage forms comprises the antiviral agent anddoes not comprise the HDACi.
 81. The kit of claim 76, wherein four ofthe plurality of oral dosage forms comprises the antiviral agent anddoes not comprise the HDACi.
 82. The kit of claim 76, wherein five ofthe plurality of oral dosage forms comprises the antiviral agent anddoes not comprise the HDACi.
 83. The kit of any one of claims 56 to 82,wherein the HDACi comprises nanatinostat and the antiviral agentcomprise valganciclovir.